Quinazoline derivatives as angiogenesis inhibitors

ABSTRACT

The invention relates to the use of compounds of formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which optionally may contain 1–3 heteroatoms selected independently from O, N and S; Z is —O—, —NH—, —S—, —CH 2 — or a direct bond; n is 0–5; m is 0–3; R 2  represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylsulphanyl, —NR 3 R 4  (wherein R 3  and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or R 5 X 1 — (wherein X 1  and R 5  are as defined herein; R 1  represents hydrogen, oxo, halogeno, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkoxymethyl, C 1-4 alkanoyl, C 1-4 haloalkyl, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 alkanoyloxy, nitro, C 1-4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphanyl, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, carbamoyl, N—C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkylcarbamoyl, aminosulphonyl, N—C 1-4 alkylaminosulphonyl, N,N-di(C 1-4 alkyl)aminosulphonyl, N—(C 1-4 alkylsulphonyl)amino, N—(C 1-4 alkylsulphonyl)-N—(C 1-4 alkyl)amino, N,N-di(C 1-4 alkylsulphonyl)amino, a C 3-7 alkylene chain joined to two ring C carbon atoms, C 1-4 alkanoylaminoC 1-4 alkyl, carboxy or a group R 56 X 10  (wherein X 10  and R 56  are as defined herein); and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

This application is the National Phase of International ApplicationPCT/GB00/00373 filed Feb. 8, 2000 which designated the U.S. and thatInternational Application.

The present invention relates to quinazoline derivatives, processes fortheir preparation, pharmaceutical compositions containing them as activeingredient, methods for the treatment of disease states associated withangiogenesis and/or increased vascular permeability, to their use asmedicaments and to their use in the manufacture of medicaments for usein the production of antiangiogenic and/or vascular permeabilityreducing effects in warm-blooded animals such as humans.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57–66; Folkman,1995, Nature Medicine 1: 27–31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829–837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303–324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848–859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139–155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017–20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841–844). Basic FGF (bFGF) is a potent stimulator of angiogenesis (e.g.Hayek et al, 1987, Biochem. Biophys. Res. Commun. 147: 876–880) andraised levels of FGFs have been found in the serum (Fujimoto et al,1991, Biochem. Biophys. Res. Commun. 180: 386–392) and urine (Nguyen etal, 1993, J. Natl. Cancer. Inst. 85: 241–242) of patients with cancer.

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signalling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefms-like tyrosine kinase receptor, Flt or Flt1, the kinase insertdomain-containing receptor, KDR (also referred to as Flk-1), and anotherfms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fltand KDR, have been shown to bind VEGF with high affinity (De Vries etal, 1992, Science 255: 989–991; Terman et al, 1992, Biochem. Biophys.Res. Comm. 1992, 187: 1579–1586). Binding of VEGF to these receptorsexpressed in heterologous cells has been associated with changes in thetyrosine phosphorylation status of cellular proteins and calcium fluxes.

The present invention is based on the discovery of compounds thatsurprisingly inhibit the effects of VEGF, a property of value in thetreatment of disease states associated with angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation, excessive scar formation and adhesions, endometriosis,dysfunctional uterine bleeding and ocular diseases with retinal vesselproliferation. Compounds of the present invention generally possesshigher potency against VEGF receptor tyrosine kinase than againstepidermal growth factor (EGF) receptor tyrosine kinase. Compounds of theinvention which have been tested possess activity against VEGF receptortyrosine kinase such that they may be used in an amount sufficient toinhibit VEGF receptor tyrosine kinase whilst demonstrating nosignificant activity against EGF receptor tyrosine kinase. Compounds ofthe present invention generally possess higher potency against VEGFreceptor tyrosine kinase than against FGF R1 receptor tyrosine kinase.Compounds of the invention which have been tested possess activityagainst VEGF receptor tyrosine kinase such that they may be used in anamount sufficient to inhibit VEGF receptor tyrosine kinase whilstdemonstrating no significant activity against FGF R1 receptor tyrosinekinase.

According to one aspect of the present invention there is provided theuse of a compound of the formula I:

wherein:

-   ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic    moiety which moiety may be saturated or unsaturated, which may be    aromatic or non-aromatic, and which optionally may contain 1–3    heteroatoms selected independently from O, N and S;-   Z is —O—, —NH—, —S—, —CH₂— or a direct bond;-   n is an integer from 0 to 5;-   m is an integer from 0 to 3;-   R² represents hydrogen, hydroxy, halogeno, cyano, nitro,    trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR³R⁴    (wherein R and R⁴, which may be the same or different, each    represents hydrogen or C₁₋₃alkyl), or R⁵X¹— (wherein X¹ represents a    direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—,    —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁸—, —NR⁹SO₂— or —NR¹⁰— (wherein R⁶, R⁷,    R⁸, R⁹ and R¹⁰ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from one of the following    twenty-two groups:-   1) hydrogen, oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be    unsubstituted or which may be substituted with one or more groups    selected from hydroxy, fluoro, chloro, bromo and amino;-   2) C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which    R¹² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different each represents hydrogen,    C₁₋₅alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3) C₁₋₅alkylX³R¹⁶ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸—, —SO₂NR¹⁹—, —NR²⁰SO₂— or —NR²¹    (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents    hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4–6-membered    saturated heterocyclic group with 1–2 heteroatoms, selected    independently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy and    which cyclic group may bear 1 or 2 substituents selected from oxo,    hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—,    —C(O)NR²⁴—, —SO₂NR²⁵, —NR²⁶SO₂— or —NR²⁷— (wherein R²³, R²⁴, R²⁵,    R²⁶ and R²⁷ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is a 4–6-membered saturated heterocyclic group    (linked via carbon or nitrogen) with 1–2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(q)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   6) C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   7) C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   8) C₂₋₅alkynylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   9) R²⁹ (wherein R²⁹ represents a pyridone group, a phenyl group or a    5–6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1–3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹,    —NR³²C(O)R³³ (wherein R³⁰, R³¹, R³² and R³³, which may be the same    or different, each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD    (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-membered    saturated heterocyclic group with 1–2 heteroatoms, selected    independently from O, S and N, which cyclic group may bear one or    more substituents selected from C₁₋₄alkyl));-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₂₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₂₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶—, —NR³⁷SO₂— or —NR³⁸— (wherein R³⁴,    R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁹C(O)—, —C(O)NR⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (wherein R³⁹,    R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   15) C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁴C(O)—, —C(O)NR⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂— or —NR⁴⁸— (wherein R⁴⁴,    R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   16) C₁₋₄alkylX⁹C₁₋₄alkylR²⁹ (wherein X⁹ represents —O—, —S—, —SO—,    —SO₂—, —NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹, —NR⁵²SO₂— or —NR⁵³—    (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   17) C₁₋₄alkylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₄alkylR⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹ is as defined    hereinbefore, q is 0 or 1, r is 0 or 1, and R⁵⁴ and R⁵⁵ are each    independently selected from hydrogen, C₁₋₃alkyl, cyclopentyl,    cyclohexyl and a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which C₁₋₃alkyl    group may bear 1 or 2 substituents selected from oxo, hydroxy,    halogeno and C₁₋₄alkoxy and which cyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl),    with the proviso that R⁵⁴ cannot be hydrogen); and additionally    wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may    bear one or more substituents selected from hydroxy, halogeno and    amino);    -   R¹ represents hydrogen, oxo, halogeno, hydroxy, C₁₋₄alkoxy,        C₁₋₄alkyl, C₁₋₄alkoxymethyl, C₁₋₄alkanoyl, C₁₋₄haloalkyl, cyano,        amino, C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₃alkanoyloxy, nitro,        C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl,        N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl,        aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,        N,N-di(C₁₋₄alkyl)aminosulphonyl, N—(C₁₋₄alkylsulphonyl)amino,        N—(C₁₋₄alkylsulphonyl)-N—(C₁₋₄alkyl)amino,        N,N-di(C₁₋₄alkylsulphonyl)amino, a C₃₋₇alkylene chain joined to        two ring C carbon atoms, C₁₋₄alkanoylaminoC₁₋₄alkyl, carboxy or        a group R⁵⁶X¹⁰ (wherein X¹⁰ represents a direct bond, —O—,        —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—, —NR⁵⁷C(O)—,        —C(O)NR⁵⁸—, —SO₂NR⁵⁹—, —NR⁶⁰SO₂— or —NR⁶¹— (wherein R⁵⁷, R⁵⁸,        R⁵⁹, R⁶⁰ and R⁶¹ each independently represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), and R⁵⁶ is selected from one        of the following twenty-two groups:-   1) hydrogen, oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be    unsubstituted or which may be substituted with one or more groups    selected from hydroxy, fluoro, chloro, bromo and amino;-   2) C₁₋₅alkylX¹¹C(O)R⁶² (wherein X¹¹ represents —O— or —NR⁶³—(in    which R⁶³ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    R⁶² represents C₁₋₃alkyl, —NR⁶⁴R⁶⁵ or —OR⁶⁶ (wherein R⁶⁴, R⁶⁵ and    R⁶⁶ which may be the same or different each represents hydrogen,    C₁₋₅alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3) C₁₋₅alkylX¹²R⁶⁷ (wherein X¹² represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR⁶⁸C(O)—, —C(O)NR⁶⁹—, —SO₂NR⁷⁰—, —NR⁷¹SO₂— or —NR⁷²—    (wherein R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹ and R⁷² each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁶⁷ represents    hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 4–6-membered    saturated heterocyclic group with 1–2 heteroatoms, selected    independently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy and    which cyclic group may bear 1 or 2 substituents selected from oxo,    hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   4) C₁₋₅alkylX¹³C₁₋₅alkylX¹⁴R⁷³ (wherein X¹³ and X¹⁴ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR⁷⁴C(O)—,    —C(O)NR⁷⁵—, —SO₂NR⁷⁶—, —NR⁷⁷SO₂— or —NR⁷⁸— (wherein R⁷⁴, R⁷⁵, R⁷⁶,    R⁷⁷ and R⁷⁸ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R⁷³ represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   5) R⁷⁹ (wherein R⁷⁹ is a 4–6-membered saturated heterocyclic group    (linked via carbon or nitrogen) with 1–2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   6) C₁₋₅alkylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   7) C₂₋₅alkenylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   8) C₂₋₅alkynylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   9) R⁸⁰ (wherein R⁸⁰ represents a pyridone group, a phenyl group or a    5–6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1–3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents selected from hydroxy, halogeno, amino, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR⁸¹R⁸²,    —NR⁸³C(O)R⁸⁴ (wherein R⁸¹, R⁸², R⁸³ and R⁸⁴, which may be the same    or different, each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD    (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-membered    saturated heterocyclic group with 1–2 heteroatoms, selected    independently from O, S and N, which cyclic group may bear one or    more substituents selected from C₁₋₄alkyl));-   10) C₁₋₅alkylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);-   11) C₂₋₅alkenylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);-   12) C₂₋₅alkynylR⁸⁰ (wherein R⁸⁰ is as defined hereinbefore);-   13) C₁₋₅alkylX¹⁵R⁸⁰ (wherein X¹⁵ represents —O—, —S—, —SO—, —SO₂—,    —NR⁸⁵C(O)—, —C(O)NR⁸⁶—, —SO₂NR⁸⁷—, —NR⁸⁸SO₂— or —NR⁸⁹— (wherein R⁸⁵,    R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined    hereinbefore);-   14) C₂₋₅alkenylX¹⁶R⁸⁰ (wherein X¹⁶ represents —O—, —S—, —SO—, —SO₂—,    —NR⁹⁰C(O)—, —C(O)NR⁹¹—, —SO₂NR⁹²—, —NR⁹³SO₂— or —NR⁹⁴— (wherein R⁹⁰,    R⁹¹, R⁹², R⁹³ and R⁹⁴ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined    hereinbefore);-   15) C₂₋₅alkynylX¹⁷R⁸⁰ (wherein X¹⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR⁹⁵C(O)—, —C(O)NR⁹⁶—, —SO₂NR⁹⁷, —NR⁹⁸SO₂— or —NR⁹⁹— (wherein R⁹⁵,    R⁹⁶, R⁹⁷, R⁹⁸ and R⁹⁹ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined    hereinbefore);-   16) C₁₋₄alkylX¹⁸C₁₋₄alkylR⁸⁰ (wherein X¹⁸ represents —O—, —S—, —SO—,    —SO₂—, —NR¹⁰⁰C(O)—, —C(O)NR¹⁰¹—, —SO₂NR¹⁰²—, —NR¹⁰³SO₂— or —NR¹⁰⁴—    (wherein R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ and R¹⁰⁴ each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as    defined hereinbefore);-   17) C₁₋₄alkylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(Cl₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore);-   21) C₂₋₅alkynylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore); and-   22) C₁₋₄alkylR¹⁰⁵(C₁₋₄alkyl)_(x)(X¹⁸)_(y)R¹⁰⁶ (wherein X¹⁸ is as    defined hereinbefore, x is 0 or 1, y is 0 or 1, and R¹⁰⁵ and R¹⁰⁶    are each independently selected from hydrogen, C₁₋₃alkyl,    cyclopentyl, cyclohexyl and a 4–6-membered saturated heterocyclic    group with 1–2 heteroatoms, selected independently from O, S and N,    which C₁₋₃alkyl group may bear 1 or 2 substituents selected from    oxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl)    with the proviso that R¹⁰⁵ cannot be hydrogen);    and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵⁶X¹⁰— may bear one or more substituents selected from    hydroxy, halogeno and amino);    or a salt thereof, or a prodrug thereof for example an ester or an    amide, in the manufacture of a medicament for use in the production    of an antiangiogenic and/or vascular permeability reducing effect in    warm-blooded animals such as humans.

According to another aspect of the present invention there is providedthe use of compounds of the formula I:

wherein:

-   ring C is a 9–10-membered bicyclic moiety which may be saturated or    unsaturated, which may be aromatic or non-aromatic, and which    optionally may contain 1–3 heteroatoms selected independently from    O, N and S;-   Z is —O—, —NH—, —S—, —CH₂— or a direct bond;-   R¹ represents hydrogen, oxo, halogeno, hydroxy, C₁₋₄alkoxy,    C₁₋₄alkyl, C₁₋₄alkoxymethyl, C₁₋₄alkanoyl, C₁₋₄haloalkyl, cyano,    amino, C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₃alkanoyloxy, nitro,    C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl,    C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl,    N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl,    N—(C₁₋₄alkylsulphonyl)amino,    N—(C₁₋₄alkylsulphonyl)-N—(C₁₋₄alkyl)amino,    N,N-di(C₁₋₄alkylsulphonyl)amino or a C₃₋₇alkylene chain joined to    two ring C carbon atoms;-   n is an integer from 0 to 5;-   m is an integer from 0 to 3;-   R² represents hydrogen, hydroxy, halogeno, cyano, nitro,    trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR³R⁴    (wherein R³ and R⁴, which may be the same or different, each    represents hydrogen or C₁₋₃alkyl), or R⁵X¹— (wherein X¹ represents a    direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—,    —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁸—, —NR⁹SO₂— or —NR¹⁰— (wherein R⁶, R⁷,    R⁸, R⁹ and R¹⁰ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from one of the following    twenty-one groups:-   1) hydrogen or C₁₋₅alkyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro    and amino;-   2) C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (in which    R¹² represents hydrogen, C₁₋₃ alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different each represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3) C₁₋₃alkylX³R¹⁶ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸—, —SO₂NR¹⁹—, —NR²⁰SO₂— or —NR²¹—    (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents    hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5–6-membered    saturated heterocyclic group with 1–2 heteroatoms, selected    independently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy and    which cyclic group may bear 1 or 2 substituents selected from oxo,    hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);-   4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—,    —C(O)NR²⁴—, —SO₂NR²⁵—, —NR²⁶SO₂— or —NR²⁷— (wherein R²³, R²⁴, R²⁵,    R²⁶ and R²⁷ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is a 5–6-membered saturated heterocyclic group    (linked via carbon or nitrogen) with 1–2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl and C₁₋₄alkylsulphonylC₁₋₄alkyl);-   6) C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   7) C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   8) C₂₋₅alkynylR²⁸ (wherein R²⁸ is as defined hereinbefore);-   9) R²⁹ (wherein R²⁹ represents a pyridone group, a phenyl group or a    5–6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1–3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents on an available carbon atom selected from hydroxy,    halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,    C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,    trifluoromethyl, cyano, —C(O)NR³⁰R³¹ and —NR³²C(O)R³³ (wherein R³⁰,    R³¹, R³² and R³³, which may be the same or different, each    represents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₂ alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₂₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶—, —NR³⁷S₂— or —NR³⁸— (wherein R³⁴,    R³⁵, R³⁶, R³⁷ and R³⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁹C(O)—, —C(O)NR⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (wherein R³⁹,    R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   15) C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁴C(O)—, —C(O)NR⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷ SO₂— or —NR⁴⁸— (wherein    R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   16) C₁₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ represents —O—, —S—, —SO—,    —SO₂—, —NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹—, —NR⁵²SO₂— or —NR⁵³—    (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined    hereinbefore);-   17) C₁₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and salts thereof, and prodrugs thereof for example    esters, amides and sulphides, in the manufacture of a medicament for    use in the production of an antiangiogenic and/or vascular    permeability reducing effect in warm-blooded animals such as humans.

Preferably ring C is a 9–10-membered aromatic bicyclic moiety which mayoptionally contain 1–3 heteroatoms selected independently from O, N andS.

More preferably ring C is a 9–10-membered heteroaromatic bicyclic moietywhich contains 1–3 heteroatoms selected independently from O, N and S.

Particularly ring C is a 9–10-membered heteroaromatic bicyclic moietywhich contains 1 or 2 nitrogen atoms.

According to one aspect of the present invention ring C is a 9-memberedheteroaromatic bicyclic moiety which contains 1 or 2 nitrogen atoms, forexample indolyl.

According to another aspect of the present invention ring C is a10-membered heteroaromatic bicyclic moiety which contains 1 or 2nitrogen atoms, for example quinolinyl.

Especially ring C is indolyl or quinolinyl.

Preferably Z is —O—, —NH—, —S— or a direct bond.

More preferably Z is —O—, —NH- or —S—.

Particularly Z is —O— or —S—, especially —O—.

Advantageously X¹⁰ represents a direct bond, —O—, —S—, —NR⁵⁷C(O)—,—NR⁶⁰SO₂— or —NR⁶¹— (wherein R⁵⁷, R⁶⁰ and R⁶¹ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹⁰ represents a direct bond, —O—, —S—, —NR⁵⁷C(O)—, —NR⁶⁰SO₂—(wherein R⁵⁷ and R⁶⁰ each independently represents hydrogen orC₁₋₂alkyl) or NH.

More preferably X¹⁰ represents —O—, —S—, —NR⁵⁷C(O)— (wherein R⁵⁷represents hydrogen or C₁₋₂alkyl) or NH.

Particularly X¹⁰ represents —O— or —NR⁵⁷C(O)— (wherein R⁵⁷ representshydrogen or C₁₋₂alkyl), more particularly —O— or —NHC(O)—, especially—O—.

According to another aspect of the present invention X¹⁰ represents —O—or a direct bond.

Advantageously X¹² represents —O—, —S—, —SO—, —SO₂—, —NR⁶⁸C(O)—,—NR⁷¹SO₂— or —NR⁷²— (wherein R⁶⁸, R⁷¹ and R⁷² each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹² represents —O—, —S—, —SO—, —SO₂— or —NR⁷²— (wherein R⁷²represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably X¹² represents —O— or —NR⁷²— (wherein R⁷² representshydrogen or C₁₋₂alkyl).

According to another aspect of the present invention X¹² represents —O—,—SO₂—, —NR⁷¹SO₂— or —NR⁷²— (wherein R⁷¹ and R⁷² each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Advantageously X¹⁸ represents —O—, —S— or —NR¹⁰⁴— (wherein R¹⁰⁴represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹⁸ represents —O— or —NR¹⁰⁴— (wherein R¹⁰⁴ representshydrogen or C₁₋₂alkyl).

According to another aspect of the present invention X¹⁸ represents —O—,—CONR¹⁰¹— or —NR¹⁰⁴— (wherein R¹⁰¹ and R¹⁰⁴ each independentlyrepresents hydrogen or C₁₋₂alkyl).

Advantageously R⁶⁷ represents a 5–6-membered saturated heterocyclicgroup with 1–2 heteroatoms, selected independently from O, S and N,which cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 5–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₃alkyl).

Preferably R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl,imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl).

More preferably R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

Particularly R⁶⁷ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl,morpholino or thiomorpholino which group may bear 1 or 2 substituentsselected from a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Preferably R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl,imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl).

More preferably R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

Particularly R⁷⁹ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl,morpholino or thiomorpholino which group may bear 1 or 2 substituentsselected from a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Advantageously R¹⁰⁵ and R¹⁰⁶ are each independently a 4–6-memberedsaturated heterocyclic group with 1–2 heteroatoms, selectedindependently from O, S and N, which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-membered saturatedheterocyclic group with 1–2 heteroatoms, selected independently from O,S and N, which cyclic group may bear one or more substituents selectedfrom C₁₋₃alkyl).

Preferably R¹⁰⁵ and R¹⁰⁶ are each independently selected frompyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl,morpholino and thiomorpholino which group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl).

More preferably R¹⁰⁵ and R¹⁰⁶ are each independently selected frompyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino which group may bear 1 or 2 substituents selected fromoxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

Particularly R¹⁰⁵ and R¹⁰⁶ are each independently selected frompyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino which group may bear 1 or 2 substituents selected from agroup —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1and ring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Advantageously R¹ represents oxo, halogeno, hydroxy, C₁₋₄alkoxy,C₁₋₄alkyl, C₁₋₄alkoxymethyl, C₁₋₄alkanoyl, C₁₋₄haloalkyl, cyano, amino,C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₃alkanoyloxy, nitro, C₁₋₄alkanoylamino,C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphinyl,C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, N—(C₁₋₄alkylsulphonyl)amino,N—(C₁₋₄alkylsulphonyl)-N—(C₁₋₄alkyl)amino,N,N-di(C₁₋₄alkylsulphonyl)amino, a C₃₋₇alkylene chain joined to two ringC carbon atoms, C₁₋₄alkanoylaminoC₁₋₄alkyl, carboxy or a group R⁵⁶X¹⁰(wherein X¹⁰ is as defined hereinbefore and R⁵⁶ is selected from one ofthe following nine groups:

-   1) C₁₋₅alkylX¹²R⁶⁷ (wherein X¹² and R⁶⁷ are as defined    hereinbefore);-   2) R⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   3) C₁₋₅alkylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   4) C₂₋₅alkenylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   5) C₂₋₅alkynylR⁷⁹ (wherein R⁷⁹ is as defined hereinbefore);-   6) C₁₋₃alkylX¹⁸C₁₋₃alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore);-   7) C₂₋₅alkenylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore);-   8) C₂₋₅alkynylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined    hereinbefore); and-   9) C₁₋₃alkylR¹⁰⁵(C₁₋₃alkyl)_(x)(X¹⁸)_(y)R¹⁰⁶ (wherein X¹⁸, x, y,    R¹⁰⁵ and R¹⁰⁶ are as defined hereinbefore;    and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵⁶X¹⁰— may bear one or more substituents selected from    hydroxy, halogeno and amino,    with the proviso that when X¹⁰ is a direct bond R⁵⁶ is not R⁷⁹).

Preferably R¹ represents oxo, halogeno, hydroxy, C₁₋₂alkoxy, C₁₋₂alkyl,C₁₋₂alkoxymethyl, C₂₋₃alkanoyl, C₁₋₂haloalkyl, cyano, amino,C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₃alkanoyloxy, nitro, C₂₋₃alkanoylamino,C₁₋₂alkoxycarbonyl, C₁₋₂alkylsulphanyl, C₁₋₂alkylsulphinyl,C₁₋₂alkylsulphonyl, carbamoyl, N—C₁₋₂alkylcarbamoyl,N,N-di(C₁₋₂alkyl)carbamoyl, aminosulphonyl, N—C₁₋₂alkylaminosulphonyl,N,N-di(C₁₋₂alkyl)aminosulphonyl, N—(C₁₋₂alkylsulphonyl)amino,N—(C₁₋₂alkylsulphonyl)-N—(C₁₋₂alkyl)amino or a C₃₋₇alkylene chain joinedto two ring C carbon atoms.

More preferably R¹ represents oxo, hydroxy, C₁₋₂alkoxymethyl, amino,halogeno, C₁₋₂alkyl, C₁₋₂alkoxy, trifluoromethyl, cyano, nitro,C₂₋₃alkanoyl.

Particularly R¹ represents methyl, ethyl, trifluoromethyl or halogeno.

Especially R¹ represents methyl, fluoro, chloro or bromo, moreespecially methyl or fluoro.

Preferably n is an integer from 0 to 3.

More preferably n is 0, 1 or 2.

Preferably m is an integer from 0 to 2, more preferably 1 or 2, mostpreferably 2.

Advantageously X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—,—NR⁹SO₂—or —NR¹⁰— (wherein R⁶, R⁹ and R¹⁰ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹ represents a direct bond, —O—, —S—, —NR⁶C(O)—, —NR⁹SO₂—(wherein R⁶ and R⁹ each independently represents hydrogen or C₁₋₂alkyl)or NH.

More preferably X¹ represents —O—, —S—, —NR⁶C(O)— (wherein R⁶ representshydrogen or C₁₋₂alkyl) or NH.

Particularly X¹ represents —O— or —NR⁶C(O)— (wherein R⁶ representshydrogen or C, ₂alkyl), more particularly —O— or —NHC(O)—, especially—O—.

According to another aspect of the present invention X¹ represents —O—or a direct bond.

Advantageously X² represents —O— or NR¹² (wherein R¹² representshydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).

Advantageously X³ represents —O—, —S—, —SO—, —SO₂—, —NR¹⁷C(O)—, —NR²SO₂—or —NR²¹— (wherein R¹⁷, R²⁰ and R²¹ each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X³ represents —O—, —S—, —SO—, —SO₂— or —NR²¹— (wherein R²¹represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

More preferably X³ represents —O— or —NR²¹— (wherein R²¹ representshydrogen or C₁₋₂alkyl).

According to another aspect of the present invention X³ represents —O—,—SO₂—, —NR²⁰SO₂— or —NR²¹— (wherein R²⁰ and R²¹ each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Advantageously X⁴ and X⁵ which may be the same or different eachrepresents —O—, —S—, —SO—, —SO₂— or —NR²⁷— (wherein R²⁷ representshydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).

Preferably X⁴ and X⁵ which may be the same or different each represents—O—, —S— or —NR²⁷— (wherein R²⁷ represents hydrogen, C₁₋₂alkyl orC₁₋₂alkoxyethyl).

More preferably X⁴ and X⁵ which may be the same or different eachrepresents —O— or NH—.

Advantageously X⁶ represents —O—, —S— or —NR³⁸— (wherein R³⁸ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁷ represents —O— or —NR³⁸— (wherein R³⁸ represents hydrogenor C₁₋₂alkyl).

Advantageously X⁷ represents —O—, —S— or —NR⁴³— (wherein R⁴³ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁷ represents —O— or —NR⁴³— (wherein R⁴³ represents hydrogenor C₁₋₂alkyl).

Advantageously X⁸ represents —O—, —S— or —NR⁴⁸— (wherein R⁴⁸ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁸ represents —O— or —NR⁴⁸— (wherein R⁴⁸ represents hydrogenor C₁₋₂alkyl).

Advantageously X⁹ represents —O—, —S— or —NR⁵³— (wherein R⁵³ representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X⁹ represents —O— or —NR⁵³— (wherein R⁵³ represents hydrogenor C₁₋₂alkyl).

According to another aspect of the present invention X⁹ represents —O—,—CONR⁵⁰— or —NR⁵³— (wherein R⁵⁰ and R⁵³ each independently representshydrogen or C₁₋₂alkyl).

Conveniently R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl,imidazolidinyl, azetidinyl, morpholino or thiomorpholino which group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl).

Advantageously R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

In one embodiment of the present invention R²⁸ is pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino or thiomorpholino whichgroup may bear 1 or 2 substituents selected from a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Particularly R²⁸ is pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl,morpholino or thiomorpholino which group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl andC₁₋₂alkylsulphonylC₁₋₃alkyl.

According to another aspect of the present invention, preferably R²⁸ ispyrrolidinyl, piperazinyl, piperidinyl, morpholino or thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl.

Where R²⁹ is a 5–6-membered aromatic heterocyclic group, it preferablyhas 1 or 2 heteroatoms, selected from O, N and S, of which morepreferably one is N, and may be substituted as hereinbefore defined.

R²⁹ is particularly a pyridone, phenyl, pyridyl, imidazolyl, thiazolyl,thienyl, triazolyl or pyridazinyl group which group may be substitutedas hereinbefore defined, more particularly a pyridone, pyridyl,imidazolyl, thiazolyl or triazolyl group, especially a pyridone,pyridyl, imidazolyl or triazolyl group which group may be substituted ashereinbefore defined.

In one embodiment of the invention R²⁹ represents a pyridone, phenyl or5–6-membered aromatic heterocyclic group with 1 to 3 heteroatomsselected from O, N and S, which group may preferably carry up to 2substituents, more preferably up to one substituent, selected from thegroup of substituents as hereinbefore defined.

In the definition of R²⁹, conveniently substituents are selected fromhalogeno, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino,which cyclic group may bear one or more substituents selected fromC₁₋₃alkyl).

In the definition of R²⁹, more conveniently substituents are selectedfrom chloro, fluoro, methyl, ethyl and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

According to another emodiment of the present invention in thedefinition of R²⁹, conveniently substituents are selected from halogeno,C₁₋₄alkyl, C₁₋₄alkoxy and cyano, more conveniently substituents areselected from chloro, fluoro, methyl and ethyl.

Advantageously R⁵⁴ and R⁵⁵ are each independently a 4–6-memberedsaturated heterocyclic group with 1–2 heteroatoms, selectedindependently from O, S and N, which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl anda group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1and ring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₃alkyl).

Preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein fis 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl,morpholino and thiomorpholino, which cyclic group may bear one or moresubstituents selected from C₁₋₃alkyl).

More preferably R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein fis 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected frompyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

More particularly R⁵⁴ and R⁵⁵ are each selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group is unsubstituted.

Conveniently R² represents hydroxy, halogeno, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ is selected from one of the followingtwenty-two groups:

-   1) oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be unsubstituted or    which may be substituted with one or more groups selected from    fluoro, chloro and bromo, or C₂₋₅alkyl which may be unsubstituted or    substituted with one or more groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different are each C₁₋₄alkyl or    C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶    represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a    4–6-membered saturated heterocyclic group with 1–2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₃alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₅alkylR¹⁰⁷ (wherein R¹⁰⁷ is a 4–6-membered saturated    heterocyclic group with 1–2 heteroatoms, selected independently from    O, S and N, which heterocyclic group is linked to C₁₋₅alkyl through    a carbon atom and which heterocyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,    C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl)) or    C₂₋₅alkylR¹⁰⁸ (wherein R¹⁰⁸ is a 4–6membered saturated heterocyclic    group with 1–2 heteroatoms, of which one is N and the other may be    selected independently from O, S and N, which heterocyclic group is    linked to C₂₋₅alkyl through a nitrogen atom and which heterocyclic    group may bear 1 or 2 substituents selected from oxo, hydroxy,    halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,    C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,    C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkoxy, di(Cl₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl));-   7) C₃₋₄alkenylR¹⁰⁹ (wherein R¹⁰⁹ represents R¹⁰⁷ or R¹⁰⁸ as defined    hereinbefore);-   8) C₃₋₄alkynylR¹⁰⁹ (wherein R¹⁰⁹ represents R¹⁰⁷ or R¹⁰⁸ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₃₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₃₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14) C₄₋₅alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15) C₄₋₅alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₅alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore); and additionally wherein any    C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one or    more substituents selected from hydroxy, halogeno and amino].

Advantageously R² represents hydroxy, halogeno, cyano, nitro,trifluoromethyl, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ is selected from one of the followingtwenty-two groups:

-   1) C₁₋₄alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₅alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be    the same or different are each C₁₋₄alkyl or C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl    and tetrahydropyranyl, which C₁₋₃alkyl group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno and C₁₋₂alkoxy and    which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,    piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group    may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₄alkylR¹¹⁰ (wherein R¹¹⁰ is a group selected from    pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl,    azetidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl    and 1,3-dithian-2-yl, which group is linked to C₁₋₄alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl)) or C₂₋₄alkylR¹¹¹ (wherein R¹¹¹ is a group    selected from morpholino, thiomorpholino, azetidin-1-yl,    pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear    1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and    thiomorpholino, which cyclic group may bear one or more substituents    selected from C₁₋₃alkyl));-   7) C₃₋₄alkenylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined    hereinbefore);-   8) C₃₋₄alkynylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined    hereinbefore);-   9) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon    atom);-   12) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon    atom);-   13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   14)1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   15)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C ₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₄alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   21) C₂₋₄alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   22) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X, q, r, R⁵⁴ and    R⁵⁵ are as defined hereinbefore);    and additionally wherein any C₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl    group in R⁵X¹— may bear one or more substituents selected from    hydroxy, halogeno and amino].

Preferably R² represents hydroxy, halogeno, nitro, trifluoromethyl,C₁₋₃alkyl, cyano, amino or R⁵X¹— [wherein X¹ is as hereinbefore definedand R⁵ is selected from one of the following twenty groups:

-   1) C₁₋₃alkyl which may be unsubstituted or which may be substituted    with one or more groups selected from fluoro, chloro and bromo, or    C₂₋₃alkyl which may be unsubstituted or substituted with one or more    groups selected from hydroxy and amino;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl, or    2-(N-methyl-N-(butoxycarbonyl)amino)ethyl;-   3) C₂₋₃alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl    and tetrahydropyranyl which group is linked to X³ through a carbon    atom and which C₁₋₃alkyl group may bear 1 or 2 substituents selected    from hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl,    cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl,    imidazolidinyl or tetrahydropyranyl group may bear one substituent    selected from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl,    C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₂alkyl);-   5) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   6) C₁₋₃alkylR¹¹⁰ (wherein R¹¹⁰ is a group selected from    pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, imidazolidinyl,    1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and    1,3-dithian-2-yl, which group is linked to C₁₋₃alkyl through a    carbon atom and which group may bear 1 or 2 substituents selected    from oxo, hydroxy, halogeno, cyano, C₁₋₂cyanoalkyl, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl, C₁₋₂alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,    C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino,    di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,    di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,    di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino)) or C₂₋₃alkylR¹¹¹ (wherein R¹¹¹ is a group selected    from morpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl,    piperazin-1-yl and piperidino which group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₂cyanoalkyl, C₁₋₂alkyl, C₁₋₂hydroxyalkyl, C₁₋₂alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,    C₁₋₂alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,    C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,    C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group    —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a heterocyclic group selected from pyrrolidinyl,    methylpiperazinyl, piperidinyl, azetidinyl, morpholino and    thiomorpholino));-   7) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   9) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);-   10) 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);-   11) C₁₋₃alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   12) 1(R²⁹X⁷)but-2-en-4-yl (wherein X^(7 and R) ²⁹ are as defined    hereinbefore);-   13)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   14) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   15) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   16) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   17) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄ alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   18) C₂₋₃alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   19) C₂₋₃alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   20) C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴    and R⁵⁵ are as defined hereinbefore); and additionally wherein any    C₁₋₅alkyl, C₂₋₅ alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one    or more substituents selected from hydroxy, halogeno and amino].

More preferably R² represents hydroxy, C₁₋₃alkyl, amino or R⁵X¹—[whereinX¹ is as hereinbefore defined and R⁵ represents methyl, ethyl, benzyl,trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl,2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(methylamino)ethyl,3-(methylamino)propyl, 2-(ethylamino)ethyl, 3-(ethylamino)propyl,2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,2-(N,N-diethylamino)ethyl, 3-(N,N-diethylamino)propyl,2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl,1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

Particularly R² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ represents ethyl, benzyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-diethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,²-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(²-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl,1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)3-(N,N-diisopropylamino)-2-hydroxypropyl].

More particularly R² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ isas hereinbefore defined and R⁵ represents ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(methylamino)ethyl, 3-(methylamino)propyl,2-(ethylamino)ethyl, 3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-(N-methyl-N-methylsulphonylamino)ethyl,3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,2-(piperidin-2-yl)ethyl, 3-(piperidin-2-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperidin-4-yloxy)ethyl,3-(piperidin-4-yloxy)propyl, 2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(N-(2-methoxyethyl)-N-methylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,3-(ethylsulphinyl)propyl, 3-(ethylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,1-(2-pyrrolidinylethyl)piperidin-4-ylmethyl,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,1-(2-piperidinylethyl)piperidin-4-ylmethyl,1-(3-piperidinylpropyl)piperidin-4-ylmethyl,1-(2-morpholinoethyl)piperidin-4-ylmethyl,1-(3-morpholinopropyl)piperidin-4-ylmethyl,1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,1-(2-azetidinylethyl)piperidin-4-ylmethyl,1-(3-azetidinylpropyl)piperidin-4-ylmethyl,3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,(2R)-3-piperidino-2-hydroxypropyl, (2S)-3-piperidino-2-hydroxypropyl,3-pyrrolidin-1-yl-2-hydroxypropyl,(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,3-(N,N-diethylamino)-2-hydroxypropyl,(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,3-(isopropylamino)-2-hydroxypropyl,(2R)-3-(isopropylamino)-2-hydroxypropyl,(2S)-3-(isopropylamino)-2-hydroxypropyl,3-(N,N-diisopropylamino)-2-hydroxypropyl,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].

In another aspect R² represents ethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,2-methoxyethoxy, 3-methoxypropoxy, 2-(methylsulphinyl)ethoxy,2-(methylsulphonyl)ethoxy, 2-(ethylsulphinyl)ethoxy,2-(ethylsulphonyl)ethoxy, 2-(N,N-dimethylsulphamoyl)ethoxy,2-(N-methylsulphamoyl)ethoxy, 2-sulphamoylethoxy, 2-(methylamino)ethoxy,3-(methylamino)propoxy, 2-(ethylamino)ethoxy, 3-(ethylamino)propoxy,2-(N,N-dimethylamino)ethoxy, 3-(N,N-dimethylamino)propoxy,2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy,2-(N-methyl-N-methylsulphonylamino)ethoxy,3-(N-methyl-N-methylsulphonylamino)propoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-(methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy,2-(ethylpiperidino)ethoxy, 3-(ethylpiperidino)propoxy,2-((2-methoxyethyl)piperidino)ethoxy,3-((2-methoxyethyl)piperidino)propoxy,2-((2-methylsulphonyl)ethylpiperidino)ethoxy,3-((2-methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy,piperidin-4-ylmethoxy, 2-(piperidin-3-yl)ethoxy,2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy,3-(piperidin-4-yl)propoxy, 2-(piperidin-2-yl)ethoxy,3-(piperidin-2-yl)propoxy, (1-methylpiperidin-3-yl)methoxy,(1-methylpiperidin-4-yl)methoxy, (1-cyanomethylpiperidin-3-yl)methoxy,(1-cyanomethylpiperidin-4-yl)methoxy, 2-(methylpiperidin-3-yl)ethoxy,2-(methylpiperidin-4-yl)ethoxy, 2-(1-cyanomethylpiperidin-3-yl)ethoxy,2-(1-cyanomethylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy,3-(methylpiperidin-4-yl)propoxy, 3-(1-cyanomethylpiperidin-3-yl)propoxy,3-(1-cyanomethylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy,2-(ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy,3-(ethylpiperidin-4-yl)propoxy, ((2-methoxyethyl)piperidin-3-yl)methoxy,((2-methoxyethyl)piperidin-4-yl)methoxy,2-((2-methoxyethyl)piperidin-3-yl)ethoxy,2-((2-methoxyethyl)piperidin-4-yl)ethoxy,3-((2-methoxyethyl)piperidin-3-yl)propoxy,3-((2-methoxyethyl)piperidin-4-yl)propoxy,(1-(2-methylsulphonylethyl)piperidin-3-yl)methoxy,(1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy,2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy,2-(1-isopropylpiperidin-3-yl)ethoxy,2-(1-isopropylpiperidin-4-yl)ethoxy,3-(1-isopropylpiperidin-2-yl)propoxy,3-(1-isopropylpiperidin-3-yl)propoxy,3-(1-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy,3-(piperidin-4-yloxy)propoxy,2-(1-(cyanomethyl)piperidin-4-yloxy)ethoxy,3-(1-(cyanomethyl)piperidin-4-yloxy)propoxy,2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy,3-(1-(2-cyanoethyl)piperidin-4-yloxy)propoxy, 2-(piperazin-1-yl)ethoxy,3-(piperazin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,(1,3-dioxolan-2-yl)methoxy, 2-(1,3-dioxolan-2-yl)ethoxy,2-(2-methoxyethylamino)ethoxy,2-(N-(2-methoxyethyl)-N-methylamino)ethoxy,2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy,3-(N-(2-methoxyethyl)-N-methylamino)propoxy,3-(2-hydroxyethylamino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy,2-(1,2,3-triazol-2-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,2-(1,2,4-triazol-4-yl)ethoxy, 4-pyridylmethoxy, 2-(4-pyridyl)ethoxy,3-(4-pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy, 2-(4-pyridylamino)ethoxy,2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy,2-(2-oxo-imidazolidin-1-yl)ethoxy, 3-(2-oxo-imidazolidin-1-yl)propoxy,2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy,2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy,2-(2-methoxyethoxy)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 3-(methylsulphinyl)propoxy,3-(methylsulphonyl)propoxy, 3-(ethylsulphinyl)propoxy,3-(ethylsulphonyl)propoxy, 2-(5-methyl-1,2,4-triazol-1-yl)ethoxy,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethoxy,2-((N-methyl-N-4-pyridyl)amino)ethoxy, 3-(4-oxidomorpholino)propoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy,3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy,2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy,2-(tetrahydropyran-4-yloxy)ethoxy, 3-(tetrahydropyran-4-yloxy)propoxy,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yloxy,1-(2-pyrrolidinylethyl)piperidin-4-ylmethoxy,1-(3-pyrrolidinylpropyl)piperidin-4-ylmethoxy,1-(2-piperidinylethyl)piperidin-4-ylmethoxy,1-(3-piperidinylpropyl)piperidin-4-ylmethoxy,1-(2-morpholinoethyl)piperidin-4-ylmethoxy,1-(3-morpholinopropyl)piperidin-4-ylmethoxy,1-(2-thiomorpholinoethyl)piperidin-4-ylmethoxy,1-(3-thiomorpholinopropyl)piperidin-4-ylmethoxy,1-(2-azetidinylethyl)piperidin-4-ylmethoxy,1-(3-azetidinylpropyl)piperidin-4-ylmethoxy,3-morpholino-2-hydroxypropoxy, (2R)-3-morpholino-2-hydroxypropoxy,(2S)-3-morpholino-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy,(2R)-3-piperidino-2-hydroxypropoxy, (2S)-3-piperidino-2-hydroxypropoxy,3-pyrrolidin-1-yl-2-hydroxypropoxy,(2R)-3-pyrrolidin-1-yl-2-hydroxypropoxy,(2S)-3-pyrrolidin-1-yl-2-hydroxypropoxy,3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,3-(N,N-diethylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diethylamino)-2-hydroxypropoxy,(2S)-3-(N,N-diethylamino)-2-hydroxypropoxy,3-(isopropylamino)-2-hydroxypropoxy,(2R)-3-(isopropylamino)-2-hydroxypropoxy,(2S)-3-(isopropylamino)-2-hydroxypropoxy,3-(N,N-diisopropylamino)-2-hydroxypropoxy,(2R)-3-(N,N-diisopropylamino)-2-hydroxypropoxy or(2S)-3-(N,N-diisopropylamino)-2-hydroxypropoxy.

According to another aspect of the present invention conveniently R²represents hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following twenty-one groups:

-   1) C₁₋₅alkyl which may be unsubstituted or substituted with one or    more fluorine atoms, or C₂₋₅alkyl which may be unsubstituted or    substituted with one or more groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵    which may be the same or different are each C₁₋₂alkyl or    C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶    represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a    5–6-membered saturated heterocyclic group with 1–2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₃alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl    and C₁₋₄alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) C₁₋₅alkylR¹²⁹ (wherein R¹²⁹ is a 5–6-membered saturated    heterocyclic group with 1–2 heteroatoms, selected independently from    O, S and N, which heterocyclic group is linked to C₁₋₅alkyl through    a carbon atom and which heterocyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl and C₁₋₄alkylsulphonylC₁₋₄alkyl) or    C₂₋₅alkylR¹³⁰ (wherein R¹³⁰ is a 5–6-membered saturated heterocyclic    group with 1–2 heteroatoms of which one is N and the other is    selected independently from O, S and N, which heterocyclic group is    linked to C₂₋₅alkyl though a nitrogen atom and which heterocyclic    group may bear 1 or 2 substituents selected from oxo, hydroxy,    halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,    C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and C₁₋₄alkylsulphonylC₁₋₄alkyl);-   6) C₃₋₄alkenylR¹³¹ (wherein R¹³¹ represents R¹²⁹ or R¹³⁰ as defined    hereinbefore);-   7) C₃₋₄alkynylR¹³¹ (wherein R¹³¹ represents R¹²⁹ or R¹³⁰ as defined    hereinbefore);-   8) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   9) C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) C₃₋₅alkenylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   11) C₃₋₅alkynylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   12) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   13) C₄₋₅alkenylX⁷R²⁹ (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   14) C₄₋₅alkynylX⁸R²⁹ (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   15) C₂₋₃alkylX⁹C₁₋₂alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   16) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₂alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₅alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   21) C₂₋₅alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore)].

According to another aspect of the present invention advantageously R²represents hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following twenty-one groups:

-   1) C₁₋₄alkyl which may be unsubstituted or substituted with one or    more fluorine atoms, or C₂₋₄alkyl which may be unsubstituted or    substituted with 1 or 2 groups selected from hydroxy and amino;-   2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as hereinbefore defined and R¹¹    represents —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be    the same or different are each C₁₋₂alkyl or C₁₋₂alkoxyethyl));-   3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as hereinbefore defined and R¹⁶ is    a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is    linked to X³ through a carbon atom and which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and    C₁₋₂alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or    piperidinyl group may carry one substituent selected from oxo,    hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₃alkyl);-   5) C₁₋₄alkylR¹³² (wherein R¹³² is a group selected from    pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl,    1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which    group is linked to C₁₋₄alkyl through a carbon atom and which group    may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl) or    C₂₋₄alkylR¹³³ (wherein R¹³³ is a group selected from morpholino,    thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which    group may carry 1 or 2 substituents selected from oxo, hydroxy,    halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl);-   6) C₃₋₄alkenylR¹³⁴ (wherein R¹³⁴ represents R¹³² or R¹³³ as defined    hereinbefore);-   7) C₃₋₄alkynylR¹³⁴ (wherein R¹³⁴ represents R¹³² or R¹³³ as defined    hereinbefore);-   8) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   9) C₁4alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   10) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon    atom);-   11) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as    defined hereinbefore with the proviso that when R⁵ is    1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon    atom);-   12) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   13) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   14)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   15) C₂₋₃alkylX⁹C₁₋₂alkylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   16) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   17) C₂₋₃alkylX⁹C₁₋₂alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) C₂₋₄alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   21) C₂₋₄alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore)].

According to another aspect of the present invention preferably R²represents hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl, cyano,amino or R⁵X¹— [wherein X¹ is as hereinbefore defined and R⁵ is selectedfrom one of the following nineteen groups:

-   1) C₁₋₃alkyl which may be unsubstituted or substituted with one or    more fluorine atoms, or C₂₋₃alkyl which may be unsubstituted or    substituted with 1 or 2 groups selected from hydroxy and amino;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl;-   3) C₂₋₃alkylX³R¹⁶ (wherein X³ is as defined hereinbefore and R¹⁶ is    a group selected from C₁₋₂alkyl, cyclopentyl, cyclohexyl,    pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is    linked to X³ through a carbon atom and which C₁₋₂alkyl group may    bear 1 or 2 substituents selected from hydroxy, halogeno and    C₁₋₂alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or    piperidinyl group may carry one substituent selected from oxo,    hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as hereinbefore    defined and R²² represents hydrogen or C₁₋₂alkyl);-   5) C₁₋₂alkylR¹³² (wherein R¹³² is a group selected from    pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl,    1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which    group is linked to C₁₋₂alkyl through a carbon atom and which group    may carry one substituent selected from oxo, hydroxy, halogeno,    cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,    C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl) or    C₂₋₃alkylR¹³³ (wherein R¹³³ is a group selected from morpholino,    thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which    group may carry one or two substituents selected from oxo, hydroxy,    halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl and C₁₋₂alkylsulphonylC₁₋₃alkyl);-   6) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   7) C₁₋₄alkylR²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined hereinbefore);-   9)1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined hereinbefore);-   10) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined hereinbefore);-   11)1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined    hereinbefore);-   12)1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined    hereinbefore);-   13) ethylX⁹methylR²⁹ (wherein X⁹ and R²⁹ are as defined    hereinbefore);-   14) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   15) ethylX⁹C₁₋₂alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore);-   16) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   17) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more fluorine atoms or with one or two    groups selected from hydroxy, amino, C₁₋₄alkylamino,    N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl    and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   18) C₂₋₃alkenylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore); and-   19) C₂₋₃alkynylX⁹C₁₋₃alkylR²⁸ (wherein X⁹ and R²⁸ are as defined    hereinbefore)].

According to another aspect of the present invention more preferably R²represents hydroxy, C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is ashereinbefore defined and R⁵ represents methyl, ethyl, benzyl,trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,2-(N,N-dimethylamino)ethyl, 3-N,N-dimethylamino)propyl,2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, 2-(methylpiperidino)ethyl,3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3(1-isopropylpiperidin-2-yl)propyl, 3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl,2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(N-(2-methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl,3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

According to another aspect of the present invention particularly R²represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbeforedefined and R⁵ represents ethyl, benzyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(methylpiperidino)ethyl,3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl,2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(N-(2-methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl,3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl,2-(5-methyl-1,2,4-triazol-1-yl)ethyl, morpholino,2-((N-(]-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

According to another aspect of the present invention more particularlyR² represents C₁₋₃alkyl, amino or R⁵X¹— [wherein X¹ is as hereinbeforedefined and R⁵ represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(methylpiperidino)ethyl,3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,3-((2-methoxyethyl)piperidino)propyl,2-((2-methylsulphonyl)ethylpiperidino)ethyl,3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl, 2-(piperidin-4-yl)ethyl,3-(piperidin-3-yl)propyl, 3-(piperidin-4-yl)propyl,(1-methylpiperidin-3-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-cyanomethylpiperidin-3-yl)methyl,(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,2-(methylpiperidin-4-yl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,2-(1-cyanomethylpiperidin-4-yl)ethyl, 3-(methylpiperidin-3-yl)propyl,3-(methylpiperidin-4-yl)propyl, 3-(1-cyanomethylpiperidin-3-yl)propyl,3-(1-cyanomethylpiperidin-4-yl)propyl, 2-(ethylpiperidin-3-yl)ethyl,2-(ethylpiperidin-4-yl)ethyl, 3-(ethylpiperidin-3-yl)propyl,3-(ethylpiperidin-4-yl)propyl, ((2-methoxyethyl)piperidin-3-yl)methyl,((2-methoxyethyl)piperidin-4-yl)methyl,2-((2-methoxyethyl)piperidin-3-yl)ethyl,2-((2-methoxyethyl)piperidin-4-yl)ethyl,3-((2-methoxyethyl)piperidin-3-yl)propyl,3-((2-methoxyethyl)piperidin-4-yl)propyl,(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,1-isopropylpiperidin-4-ylmethyl, 2-(1-isopropylpiperidin-2-yl)ethyl,2-(1-isopropylpiperidin-3-yl)ethyl, 2-(1-isopropylpiperidin-4-yl)ethyl,3-(1-isopropylpiperidin-2-yl)propyl,3-(1-isopropylpiperidin-3-yl)propyl,3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl, (1,3-dioxolan-2-yl)methyl,2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(N-(2-methoxyethyl)-N-methylamino)ethyl, 2-(2-hydroxyethylamino)ethyl,3-(2-methoxyethylamino)propyl,3-(N-(2-methoxyethyl)-N-methylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, morpholino,2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,2-(N-methyl-N-4-pyridyl)amino)ethyl, 3-(4-oxidomorpholino)propyl,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl, 2-(2-morpholinoethoxy)ethyl,3-(2-morpholinoethoxy)propyl, 2-(tetrahydropyran-4-yloxy)ethyl,3-(tetrahydropyran-4-yloxy)propyl,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].

According to another embodiment of the present invention in anotheraspect R² represents methoxy, 2-methoxyethoxy,2-(2-methoxyethoxy)ethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy,3-methylsulphonylpropoxy, benzyloxy, 2-(tetrahydropyran-4-yloxy)ethoxy,3-(tetrahydropyran-4-yloxy)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-morpholinoethoxy,3-morpholinopropoxy, 2-(imidazol-1-yl)ethoxy, 3-(imidazol-1-yl)propoxy2-(1,1-dioxothiomorpholino)ethoxy, 3-(1,1-dioxothiomorpholino)propoxy,2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy,2-(1,2,4-triazol-1-yl)ethoxy, 2-((N-methyl-N-4-pyridyl)amino)ethoxy,2-(N,N-dimethylamino)ethoxy, 3-(N,N-dimethylamino)propoxy,2-(N-methoxyacetyl-N-methylamino)ethoxy,3-(N-methoxyacetyl-N-methylamino)propoxy, 1-methylpiperidin-3-ylmethoxy,1-methylpiperidin-4-ylmethoxy, (1-cyanomethylpiperidin-3-yl)methoxy,(1-cyanomethylpiperidin-4-yl)methoxy,2-(1-cyanomethylpiperidin-3-yl)ethoxy,2-(1-cyanomethylpiperidin-4-yl)ethoxy,3-(1-cyanomethylpiperidin-3-yl)propoxy,3-(1-cyanomethylpiperidin-4-yl)propoxy,((2-methoxyethyl)piperidin-3-yl)methoxy,((2-methoxyethyl)piperidin-4-yl)methoxy,2-N-(2-methoxyethyl)-N-methylamino)ethoxy,4-(pyrrolidin-1-yl)but-2-en-yloxy, 2-(2-oxopyrrolidin-1-yl)ethoxy,3-(2-oxopyrrolidin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy,(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-(methylpiperidino)ethoxy,3-(methylpiperidino)propoxy, 2-(ethylpiperidino)ethoxy,3-(ethylpiperidino)propoxy, 2-((2-methoxyethyl)piperidino)ethoxy,3-((2-methoxyethyl)piperidino)propoxy,1-(2-methylsulphonylethyl)piperidin-3-ylmethoxy,1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy,2-((2-methylsulphonyl)ethylpiperidino)ethoxy,3-((2-methylsulphonyl)ethylpiperidino)propoxy, piperidin-3-ylmethoxy,piperidin-4-ylmethoxy, 2-(piperidin-3-yl)ethoxy,2-(piperidin-4-yl)ethoxy, 3-(piperidin-3-yl)propoxy,3-(piperidin-4-yl)propoxy, 2-(methylpiperidin-3-yl)ethoxy,2-(methylpiperidin-4-yl)ethoxy, 3-(methylpiperidin-3-yl)propoxy,3-(methylpiperidin-4-yl)propoxy, 2-(ethylpiperidin-3-yl)ethoxy,2-(ethylpiperidin-4-yl)ethoxy, 3-(ethylpiperidin-3-yl)propoxy,3-(ethylpiperidin-4-yl)propoxy,2-((2-methoxyethyl)piperidin-3-yl)ethoxy,2-((2-methoxyethyl)piperidin-4-yl)ethoxy,3-((2-methoxyethyl)piperidin-3-yl)propoxy,3-((2-methoxyethyl)piperidin-4-yl)propoxy,2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,1-isopropylpiperidin-4-ylmethoxy, 2-(1-isopropylpiperidin-2-yl)ethoxy,2-(1-isopropylpiperidin-3-yl)ethoxy,2-(1-isopropylpiperidin-4-yl)ethoxy,3-(1-isopropylpiperidin-2-yl)propoxy,3-(1-isopropylpiperidin-3-yl)propoxy,3-(1-isopropylpiperidin-4-yl)propoxy,2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy,3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy,2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy,2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl.

Where one of the R² substituents is R⁵X¹— the substituent R⁵X¹— ispreferably at the 6- or 7-position of the quinazoline ring, morepreferably at the 7-position of the quinazoline ring.

When one of the R² substituents is at the 6-position of the quinazolinering it is preferably hydrogen, halogeno, C₁₋₃alkyl, trifluoromethyl,C₁₋₃alkoxy, C₁₋₃alkylsulphanyl or —NR³R⁴ (wherein R³ and R⁴ are asdefined hereinbefore).

When one of the R² substituents is at the 6-position of the quinazolinering it is more preferably C₁₋₃alkoxy, especially methoxy.

In another aspect of the present invention there is provided the use ofcompounds of the formula Ia:

[wherein:

-   ring C, R¹, R², n and Z are as defined hereinbefore with the    provisos that R² is not hydrogen and that Z is not CH₂ or a direct    bond; and-   R^(2a) represents hydrogen, halogeno, C₁₋₃alkyl, trifluoromethyl,    C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR^(3a)R^(4a) (wherein R^(3a) and    R^(4a), which may be the same or different, each represents hydrogen    or C₁₋₃alkyl), or R^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a) is a 4-, 5-    or 6-membered saturated heterocyclic group with 1–2 heteroatoms,    selected independently from O, S and N, which heterocyclic group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a 4–6-membered saturated heterocyclic group with 1–2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from C₁₋₄alkyl), za    is an integer from 0 to 4 and X^(1a) represents a direct bond, —O—,    —CH₂—, —S—, —SO—, —SO₂—, —NR^(6a)C(O)—, —C(O)NR^(7a)—, —SO₂NR^(8a)—,    —NR^(9a)SO₂— or —NR^(10a)— (wherein R^(6a), R^(7a), R^(8a), R^(9a)    and R^(10a) each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl));    and salts thereof, and prodrugs thereof for example esters and    amides, in the manufacture of a medicament for use in the production    of an antiangiogenic and/or vascular permeability reducing effect in    warm-blooded animals such as humans.

In another aspect of the present invention there is provided the use ofcompounds of the formula Ia:

[wherein:

-   ring C, R¹, R², n and Z are as defined hereinbefore with the    provisos that R² is not hydrogen and that Z is not CH₂ or a direct    bond; and-   R^(2a) represents hydrogen, halogeno, C₁₋₃alkyl, trifluoromethyl,    C₁₋₃alkoxy, C₁₋₃alkylsulphanyl, —NR^(3a)R^(4a) (wherein R^(3a) and    R^(4a), which may be the same or different, each represents hydrogen    or C₁₋₃alkyl), or R^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a) is a 5- or    6-membered saturated heterocyclic group with 1–2 heteroatoms,    selected independently from O, S and N, which heterocyclic group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy, za is an integer from 0    to 4 and X^(1a) represents a direct bond, —O—, —CH₂—, —S—, —SO—,    —SO₂—, —NR^(6a)C(O)—, —C(O)NR^(7a)—, —SO₂NR^(8a)—, —NR^(9a)SO₂— or    —NR^(10a)— (wherein R^(6a), R^(7a), R^(8a), R^(9a) and R^(10a) each    independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl));    and salts thereof, and prodrugs thereof for example esters, amides    and sulphides, in the manufacture of a medicament for use in the    production of an antiangiogenic and/or vascular permeability    reducing effect in warm-blooded animals such as humans.

Advantageously X^(1a) represents —O—, —S—, —NR^(6a)C(O)—, —NR^(9a)SO₂—or —NR^(10a)— (wherein R^(6a), R^(9a) and R^(10a) each independentlyrepresents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X^(1a) represents —O—, —S—, —NR^(6a)CO—, —NR^(9a)SO₂—(wherein R^(6a) and R^(9a) each independently represents hydrogen orC₁₋₂alkyl) or NH.

More preferably X^(1a) represents —O—, —S—, —NR^(6a)CO— (wherein R^(6a)represents hydrogen or C₁₋₂alkyl) or NH.

Particularly X^(1a) represents —O— or —NR^(6a)CO— (wherein R^(6a)represents hydrogen or C₁₋₂alkyl), more particularly —O— or —NHCO—,especially —O—.

Preferably za is an integer from 1 to 3.

Preferably R^(5a) is a group selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino,which cyclic group may bear one or more substituents selected fromC₁₋₃alkyl).

More preferably R^(5a) is a group selected from pyrrolidinyl,piperazinyl, piperidinyl, azetidinyl, morpholino and thiomorpholinowhich group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl,methylpiperazinyl, piperidinyl, azetidinyl, morpholino andthiomorpholino).

Particularly R^(5a) is pyrrolidinyl, piperazinyl, piperidinyl,azetidinyl, morpholino or thiomorpholino which group may bear 1 or 2substituents selected from a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, methylpiperazinyl, piperidinyl, azetidinyl,morpholino and thiomorpholino).

According to another aspect of the present invention preferably R^(5a)is a group selected from pyrrolidinyl, piperazinyl, piperidinyl,morpholino and thiomorpholino which group may carry 1 or 2 substituentsselected from oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl andC₁₋₂alkoxy.

Advantageously R^(2a) represents C₁₋₃alkyl, C₁₋₃alkoxy, amino orR^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a), X^(1a) and za are as definedhereinbefore). Another advantageous value of R^(2a) is hydrogen.

Preferably R^(2a) is methyl, ethyl, methoxy, ethoxy orR^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a), X^(1a) and za are as definedhereinbefore). Another preferred value of R^(2a) is hydrogen.

More preferably R^(2a) is methyl, ethyl, methoxy, ethoxy orR^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a) is a group selected frompyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholinowhich group may carry 1 or 2 substituents selected from oxo, hydroxy,halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and C₁₋₂alkoxy, X^(1a) is —O—,—S—, —NR^(6a)C(O)—, —NR^(9a)SO₂— (wherein R^(6a) and R^(9a) eachindependently represents hydrogen or C₁₋₂alkyl) or NH, and za is aninteger from 1 to 3).

Particularly R^(2a) represents methyl, methoxy or R^(5a)(CH₂)_(za)X^(1a)(wherein R^(5a), X^(1a) and za are as defined hereinbefore).

More particularly R^(2a) represents methoxy.

In a further aspect of the present invention there is provided the useof compounds of the formula Ib:

[wherein:

-   ring C, R¹, R², R^(2a) and n are as defined hereinbefore with the    proviso that R² is not hydrogen; and-   Zb is —O— or —S—;    and salts thereof, and prodrugs thereof for example esters, amides    and sulphides, preferably esters and amides, in the manufacture of a    medicament for use in the production of an antiangiogenic and/or    vascular permeability reducing effect in warm-blooded animals such    as humans.

Preferably Zb is —O—.

According to another aspect of the present invention there are providedcompounds of the formula II:

[wherein:

-   ring C, R¹, R², R^(2a), Zb and n are as defined hereinbefore with    the proviso that R² is not hydrogen and excluding the compounds:-   6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline,    6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline,    6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and    6,7-dimethoxy-4-(2-naphthyloxy)quinazoline;    and salts thereof, and prodrugs thereof for example esters, amides    and sulphides, preferably esters and amides.

According to another aspect of the present invention there are providedcompounds of the formula IIa:

[wherein:

-   ring C, R¹, R², R^(2a), Zb and n are as defined hereinbefore with    the proviso that R² does not have any of the following values:-   hydrogen, substituted or unsubstituted C₁₋₅alkyl, halogeno or    phenoxy and excluding the compounds:-   6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline,    6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline,    6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and    6,7-dimethoxy-4-(2-naphthyloxy)quinazoline;    and salts thereof, and prodrugs thereof for example esters, amides    and sulphides, preferably esters and amides.

According to another aspect of the present invention there are providedcompounds of the formula IIb:

[wherein:

-   ring C, R¹, R², R^(2a), Zb and n are as defined hereinbefore with    the proviso that R² does not have any of the following values:-   hydrogen, substituted or unsubstituted C₁₋₅alkyl, halogeno,    C₁₋₅alkoxy, C₂₋₅alkenyl, phenoxy or phenylC₁₋₅alkoxy;    and salts thereof, and prodrugs thereof for example esters, amides    and sulphides, preferably esters and amides.

Preferred compounds of the present invention include

-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   7-(3-(1,    1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,-   6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,-   4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,-   6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,-   (R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,-   7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,-   7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,-   6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline,-   7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline,-   7-(3-(N,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline,-   4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,-   7-(2-(N,N-diethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline,-   4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,-   7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline,    and-   7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters and amides.

Especially preferred compounds of the present invention include

-   6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-ylmethoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,-   7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline-   6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline,-   7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline,-   4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,-   7-(3-(N,N-dimethylamino)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline,-   7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,-   4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,-   7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   (2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3piperidinopropoxy)quinazoline,-   (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline,-   4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline,-   (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline,-   (2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   (2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   (2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   (2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,-   (2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,-   (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,-   (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   (2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline,-   4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline,-   (2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline,    and-   4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters and amides.

More especially preferred compounds of the present invention include

-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,-   4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,-   4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,-   4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,-   (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline,    and-   4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters and amides.

Thus preferred compounds of the present invention include those, thepreparation of which is described in Examples 23, 10, 5, 176, 7, 22, 13,15, 177, 12, 35, 47, 44, 45, 157, 52, 62, 66, 75, 159, 87, 88, 89, 167,83, 97, 101, 108, 113, 114, 121, 124, 178, 162, 165, 150 and 166,

and salts thereof especially hydrochloride salts thereof and prodrugsthereof for example esters and amides.

Thus especially preferred compounds of the present invention includethose, the preparation of which is described in Examples 2, 11, 34, 36,186, 151, 57, 54, 55, 58, 56, 60, 61, 64, 65, 67, 68, 71, 72, 74, 70,77, 79, 80, 82, 86, 122, 107, 110, 112, 117, 118, 119, 123, 161, 147,163, 164, 63, 78, 115, 320, 318, 290, 252, 292, 293, 294, 301, 299, 279,280, 305, 269, 246, 266, 267, 182, 321 and 250,

and salts thereof especially hydrochloride salts thereof and prodrugsthereof for example esters and amides.

Thus more especially preferred compounds of the present inventioninclude those, the preparation of which is described in Examples 9, 243,251, 245, 247, 249, 240, 238, 237, 239, 241, 258 and 322,

and salts thereof especially hydrochloride salts thereof and prodrugsthereof for example esters and amides.

In another embodiment, preferred compounds of the present inventioninclude

-   6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline,-   (S)-6-methoxy-7-((]-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline,-   4-(1H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline,-   6-methoxy-7-((2-piperidin-1-yl)ethoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(2-chloro-1H-benzimidazol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(1H-indazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline,-   7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(tetrahydropyran-4-yloxy)ethoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(1,2-cycloheptanebenzimidazol-5-yloxy)quinazoline,-   6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)quinazoline,-   6-methoxy-7-(3-morpholinopropoxy)-4-(3-oxo-1,2-dihydro-3H-indazol-1-yl)quinazoline,-   4-(2,3-dihydro-1H-indan-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(4-methyl-4H-1,4-benzoxazin-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((3-pyrrolidin-1-yl)propoxy)quinazoline,-   6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline,-   4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,-   6-methoxy-7-(3-morpholinopropoxy)4-(quinazolin-7-yloxy)quinazoline,-   6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline,-   7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters, amides and sulphides,    preferably esters and amides.

In another embodiment more preferred compounds of the present inventioninclude

-   6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline,-   6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,-   (R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline,-   6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-ylamino)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,-   4-(7-hydroxy-2-naphthyloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,-   6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,-   7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-7-(2—(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline,-   4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   (S)-6-methoxy-7-((2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters, amides and sulphides,    preferably esters and amides.

In another embodiment especially preferred compounds of the presentinvention include

-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-7-(3-methylsulphonylpropoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline,-   7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,-   6-methoxy-7-(3-(1-methylpiperazin-4-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,-   4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,-   6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)-quinazoline,-   6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)-quinazoline,-   7-((1-cyanomethylpiperidin-4-yl)methoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,-   4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,-   6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)4-(2-methylindol-5-yloxy)quinazoline,-   7-(3-N,N-dimethylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(1-methylpiperazin-4-yl)ethoxy)ethoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,-   6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline,-   4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters, amides and sulphides,    preferably esters and amides.

In another aspect of the present invention preferred compounds include

-   6-methoxy-7-((1-(2-methoxyethyl)piperidin-4-yl)methoxy)-4-(2-methylindol-5-yloxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(pyrrolidin-1-yl)ethylcarbamoyl)vinyl)quinazoline,-   4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(4-trifluoromethylquinolin-7-yloxy)quinazoline,-   6-methoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   4-(3-carbamoylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(1-methylpiperazin-4-yl)propoxy)quinazoline,-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters, amides and sulphides,    preferably esters and amides.

An especially preferred compound of the present invention is

-   6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline    and salts thereof especially hydrochloride salts thereof and    prodrugs thereof for example esters, amides and sulphides,    preferably esters and amides.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsfor that group.

In this specification unless stated otherwise the term “alkyl” includesboth straight and branched chain alkyl groups but references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1–6 carbon atoms, preferably 1–4 carbon atoms. The term“alkoxy” as used herein, unless stated otherwise includes “alkyl”—O—groups in which “alkyl” is as hereinbefore defined. The term “aryl” asused herein unless stated otherwise includes reference to a C₆₋₁₀ arylgroup which may, if desired, carry one or more substituents selectedfrom halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (whereinalkyl and alkoxy are as hereinbefore defined). The term “aryloxy” asused herein unless otherwise stated includes “aryl”—O— groups in which“aryl” is as hereinbefore defined. The term “sulphonyloxy” as usedherein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which“alkyl” and “aryl” are as hereinbefore defined. The term “alkanoyl” asused herein unless otherwise stated includes formyl and alkylC═O groupsin which “alkyl” is as defined hereinbefore, for example C₂alkanoyl isethanoyl and refers to CH₃C═O, C₁alkanoyl is formyl and refers to CHO.In this specification unless stated otherwise the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated the term “alkenyl”advantageously refers to chains with 2–5 carbon atoms, preferably 3–4carbon atoms. In this specification unless stated otherwise the term“alkynyl” includes both straight and branched chain alkynyl groups butreferences to individual alkynyl groups such as 2-butynyl are specificfor the straight chain version only. Unless otherwise stated the term“alkynyl” advantageously refers to chains with 2–5 carbon atoms,preferably 3–4 carbon atoms. Unless stated otherwise the term“haloalkyl” refers to an alkyl group as defined hereinbefore which bearsone or more halogeno groups, such as for example trifluoromethyl.

For the avoidance of any doubt, where R² has a value of substituted orunsubstituted C₁₋₅alkyl, R² has been selected from C₁₋₃alkyl or from agroup R⁵X¹ wherein X¹ is a direct bond or —CH₂— and R⁵ is C₁₋₅alkylwhich may be unsubstituted or which may be substituted with one or moregroups selected from hydroxy, fluoro, chloro, bromo and amino.

Within the present invention it is to be understood that a compound ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits VEGF receptor tyrosine kinase activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.The formulae drawings within this specification can represent only oneof the possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It will be appreciated that compounds of the formula I or a salt thereofmay possess an asymmetric carbon atom. Such an asymmetric carbon atom isalso involved in the tautomerism described above, and it is to beunderstood that the present invention encompasses any chiral form(including both pure enantiomers, scalemic and racemic mixtures) as wellas any tautomeric form which inhibits VEGF receptor tyrosine kinaseactivity, and is not to be limited merely to any one tautomeric form orchiral form utilised within the formulae drawings. It is to beunderstood that the invention encompasses all optical and diastereomerswhich inhibit VEGF receptor tyrosine kinase activity. It is further tobe understood that in the names of chiral compounds (R,S) denotes anyscalemic or racemic mixture while (R) and (S) denote the enantiomers. Inthe absence of (R,S), (R) or (S) in the name it is to be understood thatthe name refers to any scalemic or racemic mixture, wherein a scalemicmixture contains R and S enantiomers in any relative proportions and aracemic mixture contains R and S enantiomers in the ration 50:50.

It is also to be understood that certain compounds of the formula I andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which inhibit VEGF receptor tyrosinekinase activity.

For the avoidance of any doubt, it is to be understood that when X¹ is,for example, a group of formula —NR⁶C(O)—, it is the nitrogen atombearing the R⁶ group which is attached to the quinazoline ring and thecarbonyl (C(O)) group is attached to R⁵, whereas when X¹ is, forexample, a group of formula —C(O)NR⁷—, it is the carbonyl group which isattached to the quinazoline ring and the nitrogen atom bearing the R⁷group is attached to R⁵. A similar convention applies to the other twoatom X¹ linking groups such as —NR⁹SO₂— and —SO₂NR⁸—. When X¹ is —NR¹⁰—it is the nitrogen atom bearing the R¹⁰ group which is linked to thequinazoline ring and to R⁵. An analogous convention applies to othergroups. It is further to be understood that when X¹ represents —NR¹⁰—and R¹⁰ is C₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃alkyl moiety which islinked to the nitrogen atom of X¹ and an analogous convention applies toother groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁵ is, for example, a group of formulaC₁₋₃alkylX⁹C₁₋₃alkylR²⁹, it is the terminal C₁₋₃alkyl moiety which islinked to X¹, similarly when R⁵ is, for example, a group of formulaC₂₋₅alkenylR²⁸ it is the C₂₋₅alkenyl moiety which is linked to X¹ and ananalogous convention applies to other groups. When R⁵ is a group1-R²⁹prop-1-en-3-yl it is the first carbon to which the group R²⁹ isattached and it is the third carbon which is linked to X¹ and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁵ is, for example, R²⁸ and R²⁸ is apyrrolidinyl ring which bears a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD, itis the —O— or C₁₋₄alkyl which is linked to the pyrrolidinyl ring, unlessf and g are both 0 when it is ring D which is linked to the pyrrolidinylring and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R²⁹carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety which isattached to R²⁹ whereas when R²⁹ carries a C₁₋₄alkylamino substituent itis the amino moiety which is attached to R²⁹ and an analogous conventionapplies to other groups.

For the avoidance of any doubt, it is to be understood that when R²⁸carries a C₁₋₄alkoxyC₁₋₄alkyl substituent it is the C₁₋₄alkyl moietywhich is attached to R²⁸ and an analogous convention applies to othergroups.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic or organic acidsaffording pharmaceutically acceptable anions such as with hydrogenhalides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid. Inaddition where the compounds of formula I are sufficiently acidic,pharmaceutically acceptable salts may be formed with an inorganic ororganic base which affords a pharmaceutically acceptable cation. Suchsalts with inorganic or organic bases include for example an alkalimetal salt, such as a sodium or potassium salt, an alkaline earth metalsalt such as a calcium or magnesium salt, an ammonium salt or forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A compound of the formula I, or salt thereof, and other compounds of theinvention (as hereinafter defined) may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes include, for example, those illustrated in EuropeanPatent Applications Publication Nos. 0520722, 0566226, 0602851 and0635498. Such processes also include, for example, solid phasesynthesis. Such processes, are provided as a further feature of theinvention and are as described hereinafter. Necessary starting materialsmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.

Thus, the following processes (a) to (f) and (i) to (vi) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula III:

(wherein R² and m are as defined hereinbefore and L¹ is a displaceablemoiety), with a compound of the formula IV:

(wherein ring C, R¹, Z and n are as defined hereinbefore) to obtaincompounds of the formula I and salts thereof. A convenient displaceablemoiety L¹ is, for example, a halogeno, alkoxy (preferably C₁₋₄alkoxy),aryloxy, alkylsulphanyl, arylsulphanyl, alkoxyalkylsulphanyl orsulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy,methylsulphanyl, 2-methoxyethylsulphanyl, methanesulphonyloxy ortoluene-4-sulphonyloxy group.

The reaction is advantageously effected in the presence of a base. Sucha base is, for example, an organic amine base such as, for example,pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine or for example, analkali metal or alkaline earth metal carbonate or hydroxide, for examplesodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide. Alternatively such a base is, forexample, an alkali metal hydride, for example sodium hydride, or analkali metal or alkaline earth metal amide, for example sodium amide,sodium bis(trimethylsilyl)amide, potassium amide or potassiumbis(trimethylsilyl)amide. The reaction is preferably effected in thepresence of an inert solvent or diluent, for example an ether such astetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such astoluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidin-2-one or dimethyl sulphoxide.The reaction is conveniently effected at a temperature in the range, forexample, 10 to 150° C., preferably in the range 20 to 90° C.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide, for example hydrogen chloride,sulphuric acid, a sulphonic acid, for example methane sulphonic acid, ora carboxylic acid, for example acetic or citric acid, using aconventional procedure.

(b) Production of those compounds of formula I and salts thereof whereinat least one R² is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is—O—, —S—, —OC(O)— or —NR¹⁰— (wherein R¹⁰ independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) can be achieved by thereaction, conveniently in the presence of a base (as definedhereinbefore in process (a)) of a compound of the formula V:

(wherein ring C, Z, R¹, R² and n are as hereinbefore defined and X¹ isas hereinbefore defined in this section and s is an integer from 0 to 2)with a compound of formula VI:R⁵—L¹  (VI)(wherein R⁵ and L¹ are as hereinbefore defined), L¹ is a displaceablemoiety for example a halogeno or sulphonyloxy group such as a bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group, or L¹ may begenerated in situ from an alcohol under standard Mitsunobu conditions(“Organic Reactions”, John Wiley & Sons Inc, 1992, vol 42, chapter 2,David L Hughes). The reaction is preferably effected in the presence ofa base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), advantageously at a temperature in the range, for example10 to 150° C., conveniently at about 50° C.(c) Compounds of the formula I and salts thereof wherein at least one R²is R⁵X¹ wherein R⁵ is as defined hereinbefore and X¹ is —O—, —S—,—OC(O)— or —NR¹⁰— (wherein R¹⁰ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) may be prepared by the reaction of a compound ofthe formula VII:

with a compound of the formula VIII:R⁵—X¹—H  (VIII)(wherein L¹, R¹, R², R⁵, ring C, Z, n and s are all as hereinbeforedefined and X¹ is as hereinbefore defined in this section). The reactionmay conveniently be effected in the presence of a base (as definedhereinbefore in process (a)) and advantageously in the presence of aninert solvent or diluent (as defined hereinbefore in process (a)),advantageously at a temperature in the range, for example 10 to 150° C.,conveniently at about 100° C.(d) Compounds of the formula I and salts thereof wherein at least one R²is R⁵X¹ wherein X¹ is as defined hereinbefore and R⁵ is C₁₋₅alkylR¹¹³,wherein R¹¹³ is selected from one of the following six groups:

-   1) X¹⁹C₁₋₃alkyl (wherein X¹⁹ represents —O—, —S—, —SO₂—, —NR¹¹⁴C(O)—    or —NR¹¹⁵SO₂— (wherein R¹¹⁴ and R¹¹⁵ which may be the same or    different are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);-   2) NR¹¹⁶R¹¹⁷ (wherein R¹¹⁶ and R¹¹⁷ which may be the same or    different are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);-   3) X²⁰C₁₋₅alkylX⁵R²² (wherein X²⁰ represents —O—, —S—, —SO₂—,    —NR¹¹⁸C(O)—, —NR¹¹⁹SO₂—or —NR¹²⁰— (wherein R¹¹⁸, R¹¹⁹, and R¹²⁰    which may be the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and X⁵ and R²² are as defined hereinbefore);-   4) R²⁸ (wherein R²⁸ is as defined hereinbefore);-   5) X²¹R²⁹ (wherein X²¹ represents —O—, —S—, —SO₂—, —NR¹²¹C(O)—,    —NR¹²²SO₂—, or —NR¹²³— (wherein R¹²¹, R¹²², and R¹²³ which may be    the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined hereinbefore); and-   6) X²²C₁₋₃alkylR²⁹ (wherein X²² represents —O—, —S—, —SO₂—,    —NR¹²⁴C(O)—, —NR¹²⁵SO₂— or —NR¹²⁶— (wherein R¹²⁴, R¹²⁵ and R¹²⁶ each    independently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)    and R²⁹ is as defined hereinbefore);    and additionally R¹¹³ may be selected from the following three    groups:-   7) R²⁹ (wherein R²⁹ is as defined hereinbefore);-   8) X²²C₁₋₄alkylR²⁸ (wherein X²² and R²⁸ are as defined    hereinbefore); and-   9) R⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein q, r, X⁹, R⁵⁴ and R⁵⁵ are    as defined hereinbefore);    may be prepared by reacting a compound of the formula IX:

(wherein L¹, X¹, R¹, R², ring C, Z, n and s are as hereinbefore defined)with a compound of the formula X:R¹¹³—H  (X)(wherein R¹¹³ is as defined hereinbefore) to give a compound of theformula I or salt thereof. The reaction may conveniently be effected inthe presence of a base (as defined hereinbefore in process (a)) andadvantageously in the presence of an inert solvent or diluent (asdefined hereinbefore in process (a)), and at a temperature in the range,for example 0 to 150° C., conveniently at about 50° C.

Processes (a) and (b) are preferred over processes (c) and (d).

Process (a) is preferred over processes (b), (c) and (d).

(e) The production of those compounds of the formula I and salts thereofwherein one or more of the substituents (R²)_(m) is represented by—NR¹²⁷R¹²⁸, where one (and the other is hydrogen) or both of R¹²⁷ andR¹²⁸ are C₁₋₃alkyl, may be effected by the reaction of compounds offormula I wherein the substituent (R²)_(m) is an amino group and analkylating agent, preferably in the presence of a base as definedhereinbefore. Such alkylating agents are C₁₋₃alkyl moieties bearing adisplaceable moiety as defined hereinbefore such as C₁₋₃alkyl halidesfor example C₁₋₃alkyl chloride, bromide or iodide. The reaction ispreferably effected in the presence of an inert solvent or diluent (asdefined hereinbefore in process (a)) and at a temperature in the range,for example, 10 to 100° C., conveniently at about ambient temperature.The production of compounds of formula I and salts thereof wherein oneor more of the substituents R² is an amino group may be effected by thereduction of a corresponding compound of formula I wherein thesubstituent(s) at the corresponding position(s) of the quinazoline groupis/are a nitro group(s). The reduction may conveniently be effected asdescribed in process (i) hereinafter. The production of a compound offormula I and salts thereof wherein the substituent(s) at thecorresponding position(s) of the quinazoline group is/are a nitrogroup(s) may be effected by the processes described hereinbefore andhereinafter in processes (a–d) and (i–v) using a compound selected fromthe compounds of the formulae (I-XXII) in which the substituent(s) atthe corresponding position(s) of the quinazoline group is/are a nitrogroup(s).(f) Compounds of the formula I and salts thereof wherein X¹ is —SO— or—SO₂— may be prepared by oxidation from the corresponding compound inwhich X¹ is —S— or —SO— (when X¹ is —SO₂— is required in the finalproduct). Conventional oxidation conditions and reagents for suchreactions are well known to the skilled chemist.Synthesis of Intermediates(i) The compounds of formula III and salts thereof in which L¹ ishalogeno may for example be prepared by halogenating a compound of theformula XI:

wherein R² and m are as hereinbefore defined).

Convenient halogenating agents include inorganic acid halides, forexample thionyl chloride, phosphorus(III)chloride,phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenationreaction may be effected in the presence of an inert solvent or diluentsuch as for example a halogenated solvent such as methylene chloride,trichloromethane or carbon tetrachloride, or an aromatic hydrocarbonsolvent such as benzene or toluene, or the reaction may be effectedwithout the presence of a solvent. The reaction is conveniently effectedat a temperature in the range, for example 10 to 150° C., preferably inthe range 40 to 100° C.

The compounds of formula XI and salts thereof may, for example, beprepared by reacting a compound of the formula XII:

(wherein R², s and L¹ are as hereinbefore defined) with a compound ofthe formula VIII as hereinbefore defined. The reaction may convenientlybe effected in the presence of a base (as defined hereinbefore inprocess (a)) and advantageously in the presence of an inert solvent ordiluent (as defined hereinbefore in process (a)), advantageously at atemperature in the range, for example 10 to 150° C., conveniently atabout 100° C.

Compounds of formula XI and salts thereof wherein at least one R² isR⁵X¹ and wherein X¹ is —O—, —S—, —SO—, —SO₂—, —C(O)—, —C(O)NR⁷—,—SO₂NR⁸— or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), may for example also beprepared by the reaction of a compound of the formula XIII:

(wherein R² and s are as hereinbefore defined and X¹ is as hereinbeforedefined in this section) with a compound of the formula VI ashereinbefore defined. The reaction may for example be effected asdescribed for process (b) hereinbefore. The pivaloyloxymethyl group canthen be cleaved by reacting the product with a base such as, forexample, aqueous ammonia, triethylamine in water, an alkali metal oralkaline earth metal hydroxide or alkoxide, preferably aqueous ammonia,aqueous sodium hydroxide or aqueous potassium hydroxide, in a polarprotic solvent such as an alcohol, for example methanol or ethanol. Thereaction is conveniently effected at a temperature in the range 20 to100° C., preferably in the range 20 to 50° C.

The compounds of formula XI and salts thereof may also be prepared bycyclising a compound of the formula XIV:

(wherein R² and m, are as hereinbefore defined, and A¹ is an hydroxy,alkoxy (preferably C₁₋₄alkoxy) or amino group) whereby to form acompound of formula XI or salt thereof. The cyclisation may be effectedby reacting a compound of the formula XIV, where A¹ is an hydroxy oralkoxy group, with formamide or an equivalent thereof effective to causecyclisation whereby a compound of formula XI or salt thereof isobtained, such as[3-(dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride. Thecyclisation is conveniently effected in the presence of formamide assolvent or in the presence of an inert solvent or diluent such as anether for example 1,4-dioxan. The cyclisation is conveniently effectedat an elevated temperature, preferably in the range 80 to 200° C. Thecompounds of formula XI may also be prepared by cyclising a compound ofthe formula XIV, where A¹ is an amino group, with formic acid or anequivalent thereof effective to cause cyclisation whereby a compound offormula XI or salt thereof is obtained. Equivalents of formic acideffective to cause cyclisation include for example atri-C₁₋₄alkoxymethane, for example triethoxymethane andtrimethoxymethane. The cyclisation is conveniently effected in thepresence of a catalytic amount of an anhydrous acid, such as a sulphonicacid for example p-toluenesulphonic acid, and in the presence of aninert solvent or diluent such as for example a halogenated solvent suchas methylene chloride, trichloromethane or carbon tetrachloride, anether such as diethyl ether or tetrahydrofuran, or an aromatichydrocarbon solvent such as toluene. The cyclisation is convenientlyeffected at a temperature in the range, for example 10 to 100° C.,preferably in the range 20 to 50° C.

Compounds of formula XIV and salts thereof may for example be preparedby the reduction of the nitro group in a compound of the formula XV:

(wherein R², m and A¹ are as hereinbefore defined) to yield a compoundof formula XIV as hereinbefore defined. The reduction of the nitro groupmay conveniently be effected by any of the procedures known for such atransformation. The reduction may be carried out, for example, bystirring a solution of the nitro compound under hydrogen at 1 to 4atmospheres pressure in the presence of an inert solvent or diluent asdefined hereinbefore in the presence of a metal effective to catalysehydrogenation reactions such as palladium or platinum. A furtherreducing agent is, for example, an activated metal such as activatediron (produced for example by washing iron powder with a dilute solutionof an acid such as hydrochloric acid). Thus, for example, the reductionmay be effected by heating the nitro compound under hydrogen at 2atmospheres pressure in the presence of the activated metal and asolvent or diluent such as a mixture of water and alcohol, for examplemethanol or ethanol, at a temperature in the range, for example 50 to150° C., conveniently at about 70° C.

Compounds of the formula XV and salts thereof may for example beprepared by the reaction of a compound of the formula XVI:

(wherein R², s, L¹ and A¹ are as hereinbefore defined) with a compoundof the formula VIII as hereinbefore defined to give a compound of theformula XV. The reaction of the compounds of formulae XVI and VIII isconveniently effected under conditions as described for process (c)hereinbefore.

Compounds of formula XV and salts thereof wherein at least one R² isR⁵X¹ and wherein X¹ is —O—, —S—, —SO₂—, —C(O)—, —C(O)NR⁷—, —SO₂NR⁸— or—NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), may for example also be prepared bythe reaction of a compound of the formula XVII:

(wherein R², s and A¹ are as hereinbefore defined and X¹ is ashereinbefore defined in this section) with a compound of the formula VIas hereinbefore defined to yield a compound of formula XV ashereinbefore defined. The reaction of the compounds of formulae XVII andVI is conveniently effected under conditions as described for process(b) hereinbefore.

The compounds of formula III and salts thereof wherein at least one R²is R⁵X¹ and wherein X¹ is —CH₂— may be prepared for example as describedabove from a compound of the formula XV (in which R² is —CH₃) or XIII(in which HX¹— is —CH₃), by radical bromination or chlorination to givea —CH₂Br or —CH₂Cl group which may then be reacted with a compound ofthe formula R⁵—H under standard conditions for such substitutionreactions.

The compounds of formula III and salts thereof wherein at least one R²is R⁵X¹ and wherein X¹ is a direct bond may be prepared for example asdescribed above from a compound of the formula XI, wherein the R⁵ groupis already present in the intermediate compounds (for example in acompound of the formula XV) used to prepare the compound of formula XI.

The compounds of formula III and salts thereof wherein at least one R²is R⁵X¹ and wherein X¹ is —NR⁶C(O)— or —NR⁹SO₂— may be prepared forexample from a compound of the formula XIII in which HX¹— is an —NHR⁶—or—NHR⁹— group (prepared for example from an amino group (laterfunctionalised if necessary) by reduction of a nitro group) which isreacted with an acid chloride or sulfonyl chloride compound of theformula R⁵COCl or R⁵SO₂Cl.

The compounds of formula III and salts thereof wherein at least one R²is R⁵X¹ and wherein X¹ is —O—, —S—, —SO₂—, —OC(O)—, —C(O)NR⁷—, —SO₂NR⁸—or —NR¹⁰— (wherein R⁷, R⁸ and R¹⁰ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), may also be prepared forexample by reacting a compound of the formula XVIII:

(wherein R² and s are as hereinbefore defined, X¹ is as hereinbeforedefined in this section and L² represents a displaceable protectingmoiety) with a compound of the formula VI as hereinbefore defined,whereby to obtain a compound of formula III in which L¹ is representedby L².

A compound of formula XVIII is conveniently used in which L² representsa phenoxy group which may if desired carry up to 5 substituents,preferably up to 2 substituents, selected from halogeno, nitro andcyano. The reaction may be conveniently effected under conditions asdescribed for process (b) hereinbefore.

The compounds of formula XVIII and salts thereof may for example beprepared by deprotecting a compound of the formula XIX:

(wherein R², s and L² are as hereinbefore defined, P¹ is a protectinggroup and X¹ is as hereinbefore defined in the section describingcompounds of the formula XVIII). The choice of protecting group P¹ iswithin the standard knowledge of an organic chemist, for example thoseincluded in standard texts such as “Protective Groups in OrganicSynthesis” T. W. Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, includingN-sulphonyl derivatives (for example, p-toluenesulphonyl), carbamates(for example, t-butyl carbonyl), N-alkyl derivatives (for example,2-chloroethyl, benzyl) and amino acetal derivatives (for examplebenzyloxymethyl). The removal of such a protecting group may be effectedby any of the procedures known for such a transformation, includingthose reaction conditions indicated in standard texts such as thatindicated hereinbefore, or by a related procedure. Deprotection may beeffected by techniques well known in the literature, for example whereP¹ represents a benzyl group deprotection may be effected byhydrogenolysis or by treatment with trifluoroacetic acid.

One compound of formula III may if desired be converted into anothercompound of formula III in which the moiety L¹ is different. Thus forexample a compound of formula III in which L¹ is other than halogeno,for example optionally substituted phenoxy, may be converted to acompound of formula III in which L¹ is halogeno by hydrolysis of acompound of formula III (in which L¹ is other than halogeno) to yield acompound of formula XI as hereinbefore defined, followed by introductionof halide to the compound of formula XI, thus obtained as hereinbeforedefined, to yield a compound of formula III in which L¹ representshalogen.

(ii) Compounds of formula IV and salts thereof in which ring C is anindolyl may be prepared by any of the methods known in the art, such asfor example those described in “Indoles Part I”, “Indoles Part II”, 1972John Wiley & Sons Ltd and “Indoles Part III” 1979, John Wiley & SonsLtd, edited by W. J. Houlihan.

Examples of the preparation of indoles are given in the Exampleshereinafter, such as Examples 48, 237, 242, 250 and 291.

Compounds of formula IV and salts thereof in which ring C is aquinolinyl may be prepared by any of the methods known in the art, suchas for example those described in “The Chemistry of HeterocyclicCompounds: Quinolines Parts I, II and III”, 1982 (Intersciencepublications) John Wiley & Sons Ltd, edited by G. Jones, and in“Comprehensive Heterocyclic Chemistry Vol II by A. R. Katritzky”, 1984Pergamon Press, edited by A. J. Boulton and A McKillop.

(iii) Compounds of formula V as hereinbefore defined and salts thereofmay be made by deprotecting the compound of formula XX:

(wherein ring C, Z, R¹, R², P¹, n and s are as hereinbefore defined andX¹ is as hereinbefore defined in the section describing compounds of theformula V) by a process for example as described in (i) above.

Compounds of the formula XX and salts thereof may be made by reactingcompounds of the formulae XIX and IV as hereinbefore defined, under theconditions described in (a) hereinbefore, to give a compound of theformula XX or salt thereof.

(iv) Compounds of the formula VII and salts thereof may be made byreacting a compound of the formula XXI:

(wherein R², s and each L¹ are as hereinbefore defined and the L¹ in the4-position and the other L¹ in a further position on the quinazolinering may be the same or different) with a compound of the formula IV ashereinbefore defined, the reaction for example being effected by aprocess as described in (a) above.(v) Compounds of formula IX as defined hereinbefore and salts thereofmay for example be made by the reaction of compounds of formula V asdefined hereinbefore with compounds of the formula XXII:L¹—C₁₋₅alkyl-L¹  (XXII)(wherein L¹ is as hereinbefore defined) to give compounds of formula IXor salts thereof. The reaction may be effected for example by a processas described in (b) above.

(vi) Intermediate compounds wherein X¹ is —SO— or —SO₂— may be preparedby oxidation from the corresponding compound in which X¹ is —S— or —SO—(when X¹ is —SO₂— is required in the final product). Conventionaloxidation conditions and reagents for such reactions are well known tothe skilled chemist.

When a pharmaceutically acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with, for example, an acid using a conventional procedure, theacid having a pharmaceutically acceptable anion.

Many of the intermediates defined herein, for example, those of theformulae V, VII, IX and XX are novel and these are provided as a furtherfeature of the invention. The preparation of these compounds is asdescribed herein and/or is by methods well known to persons skilled inthe art of organic chemistry.

The identification of compounds which potently inhibit the tyrosinekinase activity associated with VEGF receptors such as Flt and/or KDRand which inhibit angiogenesis and/or increased vascular permeability isdesirable and is the subject of the present invention. These propertiesmay be assessed, for example, using one or more of the procedures setout below:

(a) In Vitro Receptor Tyrosine Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit tyrosinekinase activity. DNA encoding VEGF, FGF or EGF receptor cytoplasmicdomains may be obtained by total gene synthesis (Edwards M,International Biotechnology Lab 5(3), 19–25, 1987) or by cloning. Thesemay then be expressed in a suitable expression system to obtainpolypeptide with tyrosine kinase activity. For example VEGF, FGF and EGFreceptor cytoplasmic domains, which were obtained by expression ofrecombinant protein in insect cells, were found to display intrinsictyrosine kinase activity. In the case of the VEGF receptor Flt (Genbankaccession number X51602), a 1.7 kb DNA fragment encoding most of thecytoplasmic domain, commencing with methionine 783 and including thetermination codon, described by Shibuya et al (Oncogene, 1990, 5:519–524), was isolated from cDNA and cloned into a baculovirustransplacement vector (for example pAcYM1 (see The BaculovirusExpression System: A Laboratory Guide, L. A. King and R. D. Possee,Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available fromInvitrogen Corporation)). This recombinant construct was co-transfectedinto insect cells (for example Spodoptera frugiperda 21 (Sf21)) withviral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.(Details of the methods for the assembly of recombinant DNA moleculesand the preparation and use of recombinant baculovirus can be found instandard texts for example Sambrook et al, 1989, Molecular cloning—ALaboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press andO'Reilly et al, 1992, Baculovirus Expression Vectors—A LaboratoryManual, W. H. Freeman and Co, New York). For other tyrosine kinases foruse in assays, cytoplasmic fragments starting from methionine 806 (KDR,Genbank accession number L04947), methionine 668 (EGF receptor, Genbankaccession number X00588) and methionine 399 (FGF R1 receptor, Genbankaccession number X51803) may be cloned and expressed in a similarmanner.

For expression of cFlt tyrosine kinase activity, Sf21 cells wereinfected with plaque-pure cFlt recombinant virus at a multiplicity ofinfection of 3 and harvested 48 hours later. Harvested cells were washedwith ice cold phosphate buffered saline solution (PBS) (10 mM sodiumphosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) thenresuspended in ice cold HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodiumchloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5 mM magnesiumchloride, 1 mM ethylene glycol-bis(βaminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonylfluoride); the PMSF is added just before use from a freshly-prepared 100mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. Thesuspension was centrifuged for 10 minutes at 13,000 rpm at 4° C., thesupernatant (enzyme stock) was removed and stored in aliquots at −70° C.Each new batch of stock enzyme was titrated in the assay by dilutionwith enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM sodium orthovanadate,0.1% v/v Triton X¹⁰⁰, 0.2 mM dithiothreitol). For a typical batch, stockenzyme is diluted I in 2000 with enzyme diluent and 50 μl of diluteenzyme is used for each assay well.

A stock of substrate solution was prepared from a random copolymercontaining tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (SigmaP3899), stored as 1 mg/ml stock in PBS at −20° C. and diluted 1 in 500with PBS for plate coating.

On the day before the assay 100 μl of diluted substrate solution wasdispensed into all wells of assay plates (Nunc maxisorp 96-wellimmunoplates) which were sealed and left overnight at 4° C.

On the day of the assay the substrate solution was discarded and theassay plate wells were washed once with PBST (PBS containing 0.05% v/vTween 20) and once with 50 mM Hepes pH7.4.

Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μlof diluted compound was transferred to wells in the washed assay plates.“Total” control wells contained 10% DMSO instead of compound. Twentyfive microlitres of 40 mM manganese(II)chloride containing 8 μMadenosine-5′-triphosphate (ATP) was added to all test wells except“blank” control wells which contained manganese(II)chloride without ATP.To start the reactions 50 μl of freshly diluted enzyme was added to eachwell and the plates were incubated at room temperature for 20 minutes.The liquid was then discarded and the wells were washed twice with PBST.One hundred microlitres of mouse IgG anti-phosphotyrosine antibody(Upstate Biotechnology Inc. product 05-321), diluted I in 6000 with PBSTcontaining 0.5% w/v bovine serum albumin (BSA), was added to each welland the plates were incubated for 1 hour at room temperature beforediscarding the liquid and washing the wells twice with PBST. One hundredmicrolitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Igantibody (Amersham product NXA 931), diluted 1 in 500 with PBSTcontaining 0.5% w/v BSA, was added and the plates were incubated for 1hour at room temperature before discarding the liquid and washing thewells twice with PBST. One hundred microlitres of2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution,freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodiumperborate (made with 1 phosphate citrate buffer with sodium perborate(PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added toeach well. Plates were then incubated for 20–60 minutes at roomtemperature until the optical density value of the “total” controlwells, measured at 405 nm using a plate reading spectrophotometer, wasapproximately 1.0. “Blank” (no ATP) and “total” (no compound) controlvalues were used to determine the dilution range of test compound whichgave 50% inhibtion of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (HUVEC).

HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v foetal calfserum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/vFCS+3 μg/ml heparin+1 μg/ml hydrocortisone, at a concentration of 1000cells/well in 96 well plates. After a minimum of 4 hours they were dosedwith the appropriate growth factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml orb-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4days at 37° C. with 7.5% CO₂. On day 4 the cultures were pulsed with 1μCi/well of tritiated-thymidine (Amersham product TRA 61) and incubatedfor 4 hours. The cells were harvested using a 96-well plate harvester(Tomtek) and then assayed for incorporation of tritium with a Beta platecounter. Incorporation of radioactivity into cells, expressed as cpm,was used to measure inhibition of growth factor-stimulated cellproliferation by compounds.

(c) In Vivo Solid Tumour Disease Model

This test measures the capacity of compounds to inhibit solid tumourgrowth.

CaLu-6 tumour xenografts were established in the flank of female athymicSwiss nu/nu mice, by subcutaneous injection of 1×10⁶ CaLu-6 cells/mousein 100 μl of a 50% (v/v) solution of Matrigel in serum free culturemedium. Ten days after cellular implant, mice were allocated to groupsof 8–10, so as to achieve comparable group mean volumes. Tumours weremeasured using vernier calipers and volumes were calculated as:(l×w)×√(l×w)×(π/6), where l is the longest diameter and w the diameterperpendicular to the longest. Test compounds were administered orallyonce daily for a minimum of 21 days, and control animals receivedcompound diluent. Tumours were measured twice weekly. The level ofgrowth inhibition was calculated by comparison of the mean tumour volumeof the control group versus the treatment group using a Student T testand/or a Mann-Whitney Rank Sum Test. The inhibitory effect of compoundtreatment was considered significant when p<0.05.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula Ias defined hereinbefore or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) forexample as a sterile solution, suspension or emulsion, for topicaladministration for example as an ointment or cream or for rectaladministration for example as a suppository. In general the abovecompositions may be prepared in a conventional manner using conventionalexcipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5–5000 mg per squaremeter body area of the animal, i.e. approximately 0.1–100 mg/kg. A unitdose in the range, for example, 1–100 mg/kg, preferably 1–50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1–250 mg of active ingredient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

We have found that compounds of the present invention inhibit VEGFreceptor tyrosine kinase activity and are therefore of interest fortheir antiangiogenic effects and/or their ability to cause a reductionin vascular permeability.

A further feature of the present invention is a compound of formula I,or a pharmaceutically acceptable salt thereof, for use as a medicament,conveniently a compound of formula I, or a pharmaceutically acceptablesalt thereof, for use as a medicament for producing an antiangiogenicand/or vascular permeability reducing effect in a warm-blooded animalsuch as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of an antiangiogenic and/or vascular permeability reducingeffect in a warm-blooded-animal such as a human being.

According to a further feature of the invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal, such as a human being, in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1–50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The antiangiogenic and/or vascular permeability reducing treatmentdefined hereinbefore may be applied as a sole therapy or may involve, inaddition to a compound of the invention, one or more other substancesand/or treatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. In the field of medical oncology it isnormal practice to use a combination of different forms of treatment totreat each patient with cancer. In medical oncology the othercomponent(s) of such conjoint treatment in addition to theantiangiogenic and/or vascular permeability reducing treatment definedhereinbefore may be: surgery, radiotherapy or chemotherapy. Suchchemotherapy may cover three main categories of therapeutic agent:

-   (i) other antiangiogenic agents that work by different mechanisms    from those defined hereinbefore (for example linomide, inhibitors of    integrin αvβ3 function, angiostatin, razoxin, thalidomide), and    including vascular targeting agents (for example combretastatin    phosphate and the vascular damaging agents described in    International Patent Application Publication No. WO 99/02166 the    entire disclosure of which document is incorporated herein by    reference, (for example N-acetylcolchinol-O-phosphate));-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LHRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors); and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites (for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincristine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan, and also irinotecan); also enzymes (for example    asparaginase); and thymidylate synthase inhibitors (for example    raltitrexed);    and additional types of chemotherapeutic agent include:-   (iv) biological response modifiers (for example interferon); and-   (v) antibodies (for example edrecolomab).

For example such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of a compound offormula I as defined hereinbefore, and a vascular targeting agentdescribed in WO 99/02166 such as N-acetylcolchinol-O-phosphate (Exampe 1of WO 99/02166).

As stated above the compounds defined in the present invention are ofinterest for their antiangiogenic and/or vascular permeability reducingeffects. Such compounds of the invention are expected to be useful in awide range of disease states including cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation, excessive scar formation and adhesions, endometriosis,dysfunctional uterine bleeding and ocular diseases with retinal vesselproliferation. In particular such compounds of the invention areexpected to slow advantageously the growth of primary and recurrentsolid tumours of, for example, the colon, breast, prostate, lungs andskin. More particularly such compounds of the invention are expected toinhibit the growth of those primary and recurrent solid tumours whichare associated with VEGF, especially those tumours which aresignificantly dependent on VEGF for their growth and spread, includingfor example, certain tumours of the colon, breast, prostate, lung, vulvaand skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof VEGF receptor tyrosine kinase activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:—

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18–25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus, an oil-bath apparatus or aKoffler hot plate apparatus.

(vi) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet;

(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(viii) HPLC were run under 2 different conditions:

-   1) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm column, eluting with a    gradient of methanol in water (containing 1% acetic acid) 20 to 100%    in 5 minutes. Flow rate 1.4 ml/minute. Detection: U.V. at 254 nm and    light scattering detections;-   2) on a TSK Gel super ODS 2 μM 4.6 mm×5 cm column, eluting with a    gradient of methanol in water (containing 1% acetic acid) 0 to 100%    in 7 minutes. Flow rate 1.4 ml/minute. Detection: U.V. at 254 nm and    light scattering detections.    -   (ix) petroleum ether refers to that fraction boiling between        40–60° C.    -   (x) the following abbreviations have been used:—        -   DMF N,N-dimethylformamide        -   DMSO dimethylsulphoxide        -   TFA trifluoroacetic acid        -   NMP 1-methyl-2-pyrrolidinone        -   THF tetrahydrofuran        -   HMDS 1,1,1,3,3,3-hexamethyldisilazane.        -   HPLC RT HPLC retention time        -   DEAD diethyl azodicarboxylate        -   DMA dimethylacetamide        -   DMAP 4-dimethylaminopyridine

EXAMPLE 1

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), potassium carbonate (106 mg, 0.77 mmol) and6-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperature. Thereaction mixture was treated with 1M aqueous sodium hydroxide solution(40 ml) and stirred at ambient temperature for a few minutes. The crudesolid was collected by filtration and washed with water. The resultantsolid was dissolved in dichloromethane (2 ml) and filtered through phaseseparating paper. The filtrate was evaporated under vacuum and theresidue was triturated with ether, collected by filtration and dried togive 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline(163 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.40(m, 4H); 2.48(t, 2H); 3.59(m,4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s, 1H); 7.58(m, 1H); 7.62(s, 1H);7.74(dd, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.38(d, 1H); 8.55(s, 1H);8.92(m, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis: Found C 65.9 H 5.7 N 12.4 C₂₅H₂₆N₄O₄ 0.5H₂O RequiresC 65.9 H 6.0 N 12.3%

The starting material was prepared as follows:

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol),(J. Med. Chem. 1977, vol 20, 146–149), and Gold's reagent (7.4 g, 0.05mol) in dioxane (100ml) was stirred and heated at reflux for 24 hours.Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol)were added to the reaction mixture and it was heated for a further 3hours. The volatiles were removed by evaporation, water was added to theresidue, the solid was collected by filtration, washed with water anddried. Recrystallisation from acetic acid gave7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).

7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (35 g, 124 mmol) wassuspended in thionyl chloride (440 ml) and DMF (1.75 ml) and heated atreflux for 4 hours. The thionyl chloride was evaporated under vacuum andthe residue azeotroped with toluene three times. The residue wasdissolved in NMP (250 ml) to give a solution of7-benzyloxy-4-chloro-6methoxyquinazoline.

Phenol (29.05 g, 309 mmol) was dissolved in NMP (210 ml), sodium hydride(11.025 g, 60% dispersion in mineral oil) was added in portions withcooling and the mixture was stirred for 3 hours. The viscous suspensionwas diluted with NMP (180 ml) and stirred overnight. The solution of7-benzyloxy-4-chloro-6-methoxyquinazoline was added and the suspensionstirred at 100° C. for 2.5 hours. The suspension was allowed to cool toambient temperature and poured into water (1.51) with vigorous stirring.The precipitate was collected by filtration, washed with water and driedunder vacuum. The residue was dissolved in dichloromethane, washed withbrine and filtered through phase separating paper. The filtrate wasevaporated under vacuum then triturated with ether to give7-benzyloxy-6-methoxy-4-phenoxyquinazoline (87.8 g, 83%) as a pale creamsolid.

¹H NMR Spectrum: (CDCl₃) 4.09(s, 3H); 5.34(s, 2H); 7.42(m, 12H); 7.68(s,1H)

MS (ESI): 359 (MH)⁺

7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (36.95 g, 105.5 mmol) wassuspended in TFA (420 ml) and heated at reflux for 3 hours. The reactionmixture was allowed to cool and evaporated under vacuum. The residue wasstirred mechanically in water then basified with saturated aqueoussodium hydrogen carbonate solution and stirred overnight. The water wasdecanted and the solid suspended in acetone. After stirring the whitesolid was collected by filtration, washed with acetone and dried to give7-hydroxy-6-methoxy-4-phenoxyquinazoline (26.61 g, 96%).

¹H NMR Spectrum: (DMSOd₆) 3.97(s, 3H); 7.22(s, 1H); 7.30(m, 3H); 7.47(t,2H); 7.56(s, 1H); 8.47(s, 1H); 10.70(s, 1H)

MS (ESI): 269 (MH)⁺

Morpholine (52.2 ml, 600 mmol) and 1-bromo-3-chloropropane (30 ml, 300mmol) were dissolved in dry toluene (180 ml) and heated to 70° C. for 3hours. The solid was removed by filtration and the filtrate evaporatedunder vacuum. The resulting oil was decanted from the additional solidresidue and the oil was vacuum distilled to yield1-chloro-3-morpholinopropane (37.91 g, 77%) as an oil.

¹H NMR Spectrum: (DMSOd₆) 1.85(m, 2H); 2.30(t, 4H); 2.38(t, 2H); 3.53(t,4H); 3.65(t, 2H)

MS (ESI): 164 (MH)⁺

7-Hydroxy-6-methoxy-4-phenoxyquinazoline (25.27 g, 0.1 mol) and1-chloro-3-morpholinopropane (18.48 g, 0.11 mol) were taken up in DMF(750 ml) and potassium carbonate (39.1 g, 0.33 mol) was added. Thesuspension was heated at 90° C. for 3 hours then allowed to cool. Thesuspension was filtered and the volatiles were removed by evaporation.The residue was triturated with ethyl acetate and6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (31.4 g, 84%) wascollected by filtration as a yellow crystalline solid.

¹H NMR Spectrum: (DMSOd₆) 1.97(m, 2H); 2.39(t, 4H); 2.47(t, 2H); 3.58(t,4H); 3.95(s, 3H); 4.23(t, 2H); 7.31(m, 3H); 7.36(s, 1H); 7.49(t, 2H);7.55(s, 1H); 8.52(s, 1H)

MS (ESI): 396 (MH)⁺

6-Methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (33.08 g, 84mmol) was dissolved in 6M aqueous hydrochloric acid (800 ml) and heatedat reflux for 1.5 hours. The reaction mixture was decanted andconcentrated to 250 ml then basified (pH9) with saturated aqueous sodiumhydrogen carbonate solution. The aqueous layer was extracted withdichloromethane (4×400 ml), the organic layer was separated and filteredthrough phase separating paper. The solid was triturated with ethylacetate to give6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g,89%) as a white solid.

¹H NMR Spectrum: (DMSOd₆) 1.91(m, 2H); 2.34(t, 4H); 2.42(t, 2H); 3.56(t,4H); 3.85(s, 3H); 4.12(t, 2H); 7.11(s, 1H); 7.42(s, 1H); 7.96(s, 1H);12.01(s, 1H)

MS (ESI): 320 (MH)⁺

6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9 g,75 mmol) was suspended in thionyl chloride (210 ml) and DMF (1.8 ml)then heated at reflux for 1.5 hours. The thionyl chloride was removed byevaporation under vacuum and the residue azeotroped with toluene threetimes. The residue was taken up in water and basified (pH8) withsaturated aqueous sodium hydrogen carbonate solution. The aqueous layerwas extracted with dichloromethane (4×400 ml), the organic layer waswashed with water and brine then dried (MgSO₄). After filtration theorganic layer was concentrated under vacuum to give a yellow solid whichwas triturated with ethyl acetate to give4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (17.39 g, 52%) asa pale cream solid.

¹H NMR Spectrum: (CDCl₃) 2.10–2.16(m, 2H); 2.48(br s, 4H); 2.57(t, 2H);3.73(t, 4H); 4.05(s, 3H); 4.29(t, 2H); 7.36(s, 1H); 7.39(s, 1H); 8.86(s,1H)

MS-ESI: 337 [MH]+

EXAMPLE 2

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), (prepared as described for the starting material inExample 1), potassium carbonate (106 g, 0.77 mmol) and7-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperature. Thereaction mixture was treated with 1M aqueous sodium hydroxide solution(40 ml) and stirred at ambient temperature for a few minutes. The crudesolid was collected by filtration washing with water. The resultantsolid was dissolved in dichloromethane (2 ml) and filtered through phaseseparating paper. The filtrate was evaporated under vacuum to give asolid residue which was triturated with ether, filtered and dried togive 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline(116 mg, 39%).

¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 3.59(m,4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s, 1H); 7.58(m, 2H); 7.62(s, 1H);7.92(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.55(s, 1H); 8.92(m, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis: Found C 66.6 H 5.7 N 12.4 C₂₅H₂₆N₄O₄ 0.25H₂ORequires C 66.6 H 5.9 N 12.4%

EXAMPLE 3

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), (prepared as described for the starting material inExample 1), potassium carbonate (106 mg, 0.77 mmol) and 1-naphthol (111mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours thenallowed to cool to ambient temperature. The reaction mixture was treatedwith 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambienttemperature for a few minutes. The reaction mixture was extracted withethyl acetate and the organic extracts were washed with water. Theorganic extracts were dried (MgSO₄) and the solvent removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol (95/5) to give a solid which wastriturated with ether, filtered and dried to give6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline (194 mg,65%).

¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 3.59(m,4H); 4.00(s, 3H); 4.26(t, 2H); 7.40(s, 1H); 7.48(m, 2H); 7.58(m, 2H);7.74(s, 1H); 7.75(d, 1H); 7.92(d, 1H); 8.03(d, 1H); 8.42(s, 1H)

MS (ESI): 446 (MH)⁺

Elemental analysis: Found C 69.9 H 6.2 N 9.4 C₂₆H₂₇N₃O₄ Requires C 70.1H 6.1 N 9.4%

EXAMPLE 4

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), (prepared as described for the starting material inExample 1), potassium carbonate (106 mg, 0.77 mmol) and7-hydroxy-4-methylquinoline (122 mg, 0.77 mmol), (Chem. Berich. 1967,100, 2077), in DMF (7.5 ml) was stirred at 100° C. for 5 hours thenallowed to cool to ambient temperature. The reaction mixture was treatedwith 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambienttemperature for a few minutes. The crude solid was collected byfiltration washing with water. The resultant solid was dissolved indichloromethane (2 ml) and was filtered through phase separating paper.The filtrate was evaporated under vacuum to give a solid residue whichwas triturated with ether, filtered and dried to give6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline(175 mg, 57%).

¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.39(m, 4H); 2.48(t, 2H); 2.71(s,3H); 3.59(m, 4H); 4.00(s, 3H); 4.26(t, 2H); 7.40(s, 1H); 7.41(m, 1H);7.61(dd, 1H); 7.62(s, 1H); 7.90(d, 1H); 8.20(d, 1H); 8.52(s, 1H);8.78(d, 1H)

MS (ESI): 461 (MH)⁺

Elemental analysis: Found C 67.1 H 5.9 N 12.1 C₂₆H₂₈N₄O₄ 0.2H₂O RequiresC 67.3 H 6.2 N 12.1%

EXAMPLE 5

A mixture of4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline(220 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at100° C. for 5 hours then allowed to cool to ambient temperature. Thereaction mixture was treated with 1M aqueous sodium hydroxide solution(40 ml) and stirred at ambient temperature for a few minutes. The crudesolid was collected by filtration washing with water. The resultantsolid was dissolved in dichloromethane (2 ml) and was filtered throughphase separating paper. The filtrate was evaporated under vacuum to givea solid residue which was triturated with ether, filtered and dried togive7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline(205 mg, 73%).

¹H NMR Spectrum: (DMSOd₆) 1.98(m, 2H); 2.65(t, 2H); 2.92(m, 4H); 3.10(m,4H); 4.00(s, 3H); 4.28(t, 2H); 7.42(s, 1H); 7.58(m, 2H); 7.64(s, 1H);7.92(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.55(s, 1H); 8.92(m, 1H)

MS (ESI): 495 (MH)⁺

Elemental analysis: Found C 60.0 H 5.0 N 11.1 C₂₃H₂₆N₄O₅S 0.25H₂ORequires C 60.2 H 5.4 N 11.2%

The starting material was prepared as follows:

7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.3 g, 124 mmol),(prepared as described for the starting material in Example 1), wastaken up in thionyl chloride (440 ml) and DMF (1.75 ml) then heated atreflux for 4 hours. The thionyl chloride was evaporated under vacuum andthe residue azeotroped with toluene three times to give7-benzyloxy-4-chloro-6-methoxyquinazoline.

A mixture of the crude 7-benzyloxy-4-chloro-6-methoxyquinazoline,potassium carbonate (50 g, 362 mmol) and 4-chloro-2-fluorophenol (8.8ml, 83 mmol) in DMF (500 ml) was stirred at 100° C. for 5 hours thenallowed to cool to ambient temperature overnight. The reaction mixturewas poured into water (21) and was stirred at ambient temperature for afew minutes. The crude solid was collected by filtration washing withwater. The resultant solid was dissolved in dichloromethane and filteredthrough diatomaceous earth. The filtrate was treated with decolourisingcharcoal, boiled for a few minutes then filtered through diatomaceousearth. The filtrate was filtered through phase separating paper and thenevaporated under vacuum to give a solid residue which was trituratedwith ether, filtered and dried to give7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g,76%).

¹H NMR Spectrum: (DMSOd₆) 3.98(s, 3H); 5.34(s, 2H); 7.42(m, 9H);7.69(dd, 1H); 8.55(s, 1H)

MS (ESI): 411 (MH)⁺

7-Benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (1.4 g,3.4 mmol) was suspended in TFA (15 ml) and heated at reflux for 3 hours.The reaction mixture was allowed to cool, toluene was added and thevolatiles were removed by evaporation under vacuum. The residue wastriturated with ether and then acetone. The precipitate was collected byfiltration and dried to give4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (21.8 g).This was used without further purification in the next step.

¹H NMR Spectrum: (DMSOd₆) 3.97(s, 3H); 7.22(s, 1H); 7.39(d, 1H); 7.53(m,2H); 7.67(dd, 1H); 8.46(s, 1H)

MS (ESI): 321 (MH)⁺

A mixture of 3-amino-1-propanol (650 μl, 8.4 mmol) and vinyl sulphone (1g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture wasallowed to cool and was purified by column chromatography eluting withmethylene chloride/methanol (95/5) to give3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).

¹H NMR Spectrum: (CDCl₃) 1.7–1.8(m, 2H); 2.73(t, 2H); 3.06(br s, 8H);3.25(s, 1H); 3.78(t, 2H)

MS-ESI: 194 [MH]⁺

4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (5.0 g, 15.6mmol) was suspended in dichloromethane (150 ml) and tributylphosphine(11.1 ml, 44.6 mmol) was added followed by stirring at ambienttemperature for 30 minutes. To this mixture was added3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol) followed bythe addition of 1,1′-(azodicarbonyl)dipiperidine (11.7 g, 46.4 mmol) inportions. The mixture was stirred at ambient temperature overnight thendiluted with ether (300 ml) and the precipitate was removed byfiltration. The residue was chromatographed on silica eluting withdichloromethane and methanol (95/5). The relevant fractions werecombined and evaporated to give a solid which was triturated with ethylacetate filtered and dried to give4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline(5.4 g, 70%). This was used without further purification in the nextstep.

¹H NMR Spectrum: (DMSOd₆) 1.86(m, 2H); 2.65(t, 2H); 2.92(m, 4H); 3.08(m,4H); 3.97(s, 3H); 4.26(t, 2H); 7.40(m, 1H); 7.42(s, 1H); 7.56(m, 2H);7.68(dd, 1H); 8.54(s, 1H)

MS (ESI): 496 (MH)⁺

Elemental analysis: Found C 52.7 H 4.4 N 8.3 C₂₂H₂₃N₃ClFO₅S 0.25H₂ORequires C 52.8 H 4.7 N 8.4%

4-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline(3.5 g, 7 mmol) was dissolved in 2M aqueous hydrochloric acid (56 ml)and heated at 95° C. for 2 hours. The cooled reaction mixture wastreated with solid sodium hydrogen carbonate solution to give a thickpaste which was diluted with water and filtered. The solid wastransferred to a flask and azeotroped with toluene twice to give a drysolid. The solid was flash chromatographed on silica eluting withdichloromethane and methanol (95/5). The relevant fractions werecombined and evaporated to give7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(2.26 g, 87%) as a white solid.

MS (ESI): 368 (MH)⁺

7-(3-(1,1-Dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(4.2 g, 11.4 mmol) was suspended in thionyl chloride (45 ml) and DMF(0.1 ml) then heated at reflux for 2.5 hours. The residue was dilutedwith toluene, the thionyl chloride was evaporated under vacuum, theresidue was then azeotroped with toluene three times. The residue wastaken up in water and basified (pH8) with saturated aqueous sodiumhydrogen carbonate solution. The aqueous layer was extracted withdichloromethane (×4), the organic layer was washed with water and brinethen filtered through phase separating paper. The organic layer wasconcentrated under vacuum to give an orange solid. The solid was flashchromatographed on silica eluting with dichloromethane and methanol(95/5). The relevant fractions were combined and evaporated to give asolid which was triturated with ether then filtered and dried to give4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline(2.27 g, 52%).

MS (ESI): 386 (MH)⁺

EXAMPLE 6

6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (290 mg, 1.4 mmol) wassuspended in thionyl chloride (5 ml) and DMF (2 drops) and heated atreflux for 2 hours. The thionyl chloride was evaporated under vacuum andthe residue azeotroped with toluene three times to give4-chloro-6,7-dimethoxyquinazoline. A mixture of the crude4-chloro-6,7-dimethoxyquinazoline, potassium carbonate (970 mg, 7 mmol)and 7-hydroxyquinoline (235 mg, 1.62 mmol) in DMF (10 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperatureovernight. The reaction mixture was treated with 1M aqueous sodiumhydroxide solution and stirred at ambient temperature for a few minutes.The reaction mixture was extracted with ethyl acetate (×4) and theorganic extracts washed with water and brine. The organic extracts weredried (MgSO₄), filtered and the solvent removed under vacuum. Theresidue was triturated with ethyl acetate and then recrystallised fromhot ethyl acetate to give 6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline(110 mg, 24%) as a white solid.

¹H NMR Spectrum: (DMSOd₆) 4.00(s, 3H); 4.00(s, 3H); 7.40(s, 1H); 7.59(m,3H); 7.92(d, 1H); 8.08(d, 1H); 8.42(d, 1H); 8.55(s, 1H); 8.92(dd, 1H)

MS (ESI): 334 (MH)⁺

Elemental analysis: Found C 68.2 H 4.3 N 12.5 C₁₉H₁₅N₃O₃ Requires C 68.5H 4.5 N 12.6%

The starting material was prepared as follows:

A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10ml) was stirred and heated at 190° C. for 5 hours. The mixture wasallowed to cool to approximately 80° C. and water (50 ml) was added. Themixture was then allowed to stand at ambient temperature for 3 hours.The precipitate was collected by filtration, washed with water and driedto give 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).

EXAMPLE 7

A mixture of(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(183 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and7-hydroxyquinoline (111 mg, 0.77 mmol) in DMF (7 ml) was stirred at 100°C. for 5 hours and allowed to cool to ambient temperature. The reactionmixture was treated with 1M aqueous sodium hydroxide solution (30 ml)and stirred for 10 minutes. The crude solid was collected by filtrationwashing with water. The resultant solid was dissolved in dichloromethane(2 ml) and filtered through phase separating paper. The filtrate wasevaporated under vacuum to give a solid residue which was trituratedwith ether, filtered and dried to give a scalemic mixture of6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4(quinolin-7-yloxy)quinazoline(149 mg, 61%).

¹H NMR Spectrum: (DMSOd₆) 1.10(m, 1H); 1.51(m, 1H); 1.64(m, 1H); 1.85(m,3H); 2.09(m, 1H); 2.15(s, 3H); 2.62(m, 1H); 2.82(m, 1H); 3.99(s, 3H);4.09(d, 2H); 7.38(s, 1H); 7.55(m, 2H); 7.63(s, 1H); 7.91(d, 1H); 8.10(d,1H); 8.44(d, 1H); 8.54(s, 1H); 8.93(d, 1H)

MS (ESI): 431 (MH)⁺

Elemental analysis: Found C 68.7 H 5.7 N 12.8 C₂₅H₂₆N₄O₃ 0.3H₂O RequiresC 68.9 H 6.2 N 12.8%

The starting material was prepared as follows:

(R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by resolution of ethylnipecotate by treatment with L(+)-tartaric acid as described in J. Org.Chem. 1991, (56), 1168), was dissolved in 38.5% aqueous formaldehydesolution (45 ml) and formic acid (90 ml) and the mixture heated atreflux for 18 hours. The mixture was allowed to cool and added dropwiseto cooled saturated aqueous sodium hydrogen carbonate solution. Themixture was adjusted to pH12 by addition of sodium hydroxide and themixture was extracted with methylene chloride. The organic extract waswashed with brine, dried (MgSO₄) and the solvent removed by evaporationto give (R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as acolourless oil.

MS-ESI: 172 [MH]⁺

A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate (5.69 g, 33mmol) in ether (20 ml) was added dropwise to a stirred solution oflithium aluminium hydride (36.6 ml of a 1M solution in THF, 36.6 mmol)in ether (85 ml) cooled to maintain a reaction temperature of 20° C. Themixture was stirred for 1.5 hours at ambient temperature and then water(1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water(4.3 ml) were added. The insolubles were removed by filtration and thevolatiles removed from the filtrate by evaporation to give(R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless oil.

¹H NMR Spectrum: (DMSOd₆) 1.06(q, 1H); 1.51–1.94(m, 5H); 2.04(s, 3H);2.34(br s, 1H); 2.62(m, 1H); 2.78(d, 1H); 3.49(m, 1H); 3.59(m, 1H)

MS-ESI: 130 [MH]⁺

4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (12.1 g, 38mmol), (prepared as described for the starting material in Example 5),was suspended in dichloromethane (375 ml) and treated withtriphenylphosphine (29.6 g, 113 mmol) then stirred at ambienttemperature for 30 minutes. (1-Methylpiperidin-3-yl)methanol (8.25 g,63.8 mmol) and (R)-(1-methylpiperidin-3-yl)methanol (1.46 g, 11.3 mmol),(CAS 205194-11-2), giving R:S (57.5:42.5 by chiral HPLC) (9.7 g, 75mmol) were dissolved in dichloromethane (75 ml) and added to thesuspension. Diethyl azodicarboxylate (17.7 ml, 75 mmol) was added inportions using a syringe pump and the mixture was then allowed to warmto ambient temperature and stirred overnight. The residue wasconcentrated under vacuum then chromatographed on silica eluting withdichloromethane followed by dichloromethane/methanol/ammonia (93/6/1).The relevant fractions were combined and evaporated to give an oil. Theresidue was triturated with ether, filtered and dried to give(R,S)-4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(8.7 g, 53%).

¹H NMR Spectrum: (DMSOd₆) 1.11 (m, 1H); 1.50(m, 1H); 1.58–1.98(m, 4H);2.09(m, 1H); 2.15(s, 3H); 2.62(d, 1H); 2.81(d, 1H); 3.95(s, 3H); 4.09(d,2H); 7.39(m, 2H); 7.55(m, 2H); 7.67(d, 1H); 8.53(s, 1H)

MS (ESI): 432 (MH)⁺

(R,S)-4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(8.7 g, 20 mmol) was dissolved in 2M aqueous hydrochloric acid (150 ml)and heated at reflux for 1.5 hours. The reaction mixture wasconcentrated then basified (pH9) with saturated aqueous ammonia solution(0.88). The aqueous layer was extracted with dichloromethane (4×400 ml)and the organic extracts filtered through phase separating paper thenevaporated under vacuum. The solid was triturated with ether to give(R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinazolin-4-one(4.05 g, 66%) as a white solid.

¹H NMR Spectrum: (DMSOd₆) 1.05(m, 1H); 1.401.95(m, 5H); 2.02(m, 1H);2.14(s, 3H); 2.59(d, 1H); 2.78(d, 1H); 3.85(s, 3H); 3.95(d, 2H); 7.09(s,1H); 7.42(s, 1H); 7.95(s, 1H); 12.00(s, 1H)

MS (ESI): 304 (MH)⁺

(R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinazolin-4-one(2.72 g, 8.9 mmol) was suspended in thionyl chloride (90 ml) and DMF(0.5 ml) and heated at reflux for 45 minutes. The thionyl chloride wasevaporated under vacuum and the residue azeotroped with toluene threetimes. The residue was taken up in water and basified (pH8) withsaturated aqueous sodium hydrogen carbonate solution. The aqueous layerwas extracted with ethyl acetate (4×400 ml). The organic extracts werewashed with saturated aqueous sodium hydrogen carbonate solution, waterand brine then dried (MgSO₄). After filtration the organic extracts wereconcentrated under vacuum then dried overnight at 40° C. under vacuum togive(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(2.62 g, 91%) as a solid.

¹H NMR Spectrum: (DMSOd₆) 1.10(m, 1H); 1.42–1.96(m, 5H); 2.09(m, 1H);2.15(s, 3H); 2.60(d, 1H); 2.80(d, 1H); 3.98(s, 3H); 4.10(d, 2H); 7.35(s,1H); 7.42(s, 1H); 8.84(s, 1H)

MS (ESI): 322 (MH)⁺

EXAMPLE 8

(R,S)-6-Methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,(prepared as described in Example 7), was chromatographed on Chiral CELOD (250 mm×4.6 mm), (trade mark of Daicel Chemical Industries Ltd), inisohexane/ethanol/triethylamine/TFA (80/20/0.5/0.25). The relevantfractions for S (RT 12.55) and R (RT 15.88) enantiomers were eachcombined separately and worked up as follows.

The solution was evaporated under vacuum to give a liquid. This wastreated with 5M aqueous sodium hydroxide solution (15 ml) and extractedwith ethyl acetate. The organic extracts were washed with water thenbrine and filtered through phase separating paper. The filtrate wasevaporated to give(S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline(50 mg). The same method was used to give(R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline(71 mg).

EXAMPLE 9

A suspension of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g,0.4 mmol), 5-hydroxy-2-methylindole (74 mg, 0.5 mmol) and potassiumcarbonate (83 mg, 0.6 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2hours. After cooling to ambient temperature, water (20 ml) was added.The precipitate was collected by filtration, washed with water and driedunder vacuum at 60° C. to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(80 mg, 46%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9–2.0(m, 2H); 2.05–2.2(m, 2H);2.25–2.4(m, 2H); 2.43(s, 3H); 3.05–3.2(m, 2H); 3.35–3.5(m, 2H);3.65–3.75(m, 2H); 4.12(s, 3H); 4.35–4.5(t, 2H); 7.0(dd, 1H); 7.35(d,1H); 7.42(d, 1H); 7.6(s, 1H); 7.85(s, 1H); 9.15(s, 1H)

MS (ESI): 433 (MH)⁺

The starting material was prepared as follows:

A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g, 50 mmol),3-(pyrrolidin-1-yl)propyl chloride (14.75 g, 0.1 mol), (J. Am. Chem.Soc. 1955, 77, 2272), potassium carbonate (13.8 g, 0.1 mol) andpotassium iodide (1.66 g, 10 mmol) in DMF (150 ml) was stirred andheated at 100° C. for 3 hours. The mixture was allowed to cool and theinsolubles were removed by filtration and the volatiles were removedfrom the filtrate by evaporation. The residue was dissolved in ethanol(75 ml), 2M aqueous sodium hydroxide (75 ml) was added and the mixturewas heated at 90° C. for 2 hours. The mixture was concentrated byevaporation, acidified with concentrated hydrochloric acid, washed withether and then subjected to purification on a Diaion (trade mark ofMitsubishi) HP20SS resin column, eluting with water and then with agradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). Themethanol was removed by evaporation and the aqueous residue was freezedried to give 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acidhydrochloride (12.2 g, 77%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 2.2(m, 2H); 3.15(t, 2H); 3.3(t, 2H);3.5(d, 2H); 3.7(t, 2H); 3.82(s, 3H); 4.05(d, 2H); 4.15(t, 2H); 7.07(d,1H); 7.48(s, 1H); 7.59(d, 1H)

MS-EI: 279 [M^(•)]⁺

Fuming nitric acid (2.4 ml, 57.9 mmol) was added slowly at 0° C. to asolution of 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acidhydrochloride (12.15 g, 38.17 mmol) in TFA (40 ml). The cooling bath wasremoved and the reaction mixture stirred at ambient temperature for 1hour. The TFA was removed by evaporation and ice/water was added to theresidue and the solvent removed by evaporation. The solid residue wasdissolved in dilute hydrochloric acid (pH2.2), poured onto a Diaion(trade mark of Mitsubishi) HP20SS resin column and eluted with methanol(gradient 0 to 50%) in water. Concentration of the fractions byevaporation gave a precipitate which was collected by filtration anddried under vacuum over phosphorus pentoxide to give5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acidhydrochloride (12.1 g, 90%).

¹H NMR Spectrum: (DMSOd₆, TFA) 1.8–1.9 (m, 2H); 2.0–2.1(m, 2H);2.1–2.2(m, 2H); 3.0–3.1(m, 2H); 3.3(t, 2H); 3.6–3.7(m, 2H); 3.95(s, 3H);4.25(t, 2H); 7.35(s, 1H); 7.62(s, 1H)

A solution of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoicacid hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20 ml) and DMF(50 μl) was heated at 45° C. for 1.5 hours. The excess thionyl chloridewas removed by evaporation and by azeotroping with toluene (×2). Theresulting solid was suspended in THF (250 ml) and methylene chloride(100 ml) and ammonia was bubbled though the mixture for 30 minutes andthe mixture stirred for a further 1.5 hours at ambient temperature. Thevolatiles were removed by evaporation, the residue was dissolved inwater and applied to a Diaion (trade mark of Mitsubishi) HP20SS resincolumn and eluted with water/methanol (100/0 to 95/5). The solvent wasremoved by evaporation from the fractions containing product and theresidue was dissolved in a minimum of methanol and the solution wasdiluted with ether. The resulting precipitate was collected byfiltration, washed with ether and dried under vacuum to give5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g, 73%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.85–1.95(m, 2H); 2–2.1(m, 2H);2.15–2.25(m, 2H); 3.0–3.1(m, 2H); 3.31(t, 2H); 3.62(t, 2H); 3.93(s, 3H);4.2(t, 2H); 7.16(s, 1H); 7.60(s, 1H)

MS-EI: 323 μM^(•)]⁺

Concentrated hydrochloric acid (5 ml) was added to a suspension of5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (1.5 g, 4.64mmol) in methanol (20 ml) and the mixture was heated at 50° C. to give asolution. Iron powder (1.3 g, 23.2 mmol) was added in portions and thereaction mixture was then heated at reflux for 1 hour. The mixture wasallowed to cool, the insolubles were removed by filtration throughdiatomaceous earth and the volatiles were removed from the filtrate byevaporation. The residue was purified on a Diaion (trade mark ofMitsubishi) HP20SS resin column, eluting with water and then with dilutehydrochloric acid (pH2). The fractions containing product wereconcentrated by evaporation and the resulting precipitate was collectedby filtration and dried under vacuum over phosphorus pentoxide to give2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide hydrochloride(1.44 g, 85%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9(br s, 2H); 2.05(br s, 2H); 2.2(brs, 2H); 3.05(br s, 2H); 3.3(t, 2H); 3.61(br s, 2H); 3.8(s, 3H); 4.11(t,2H); 7.05(s, 1H); 7.53(s, 1H)

MS-EI: 293 [M^(•)]⁺

A mixture of 2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamidehydrochloride (5.92 g, 16.2 mmol) and Gold's reagent (3.5 g, 21.4 mmol)in dioxane (50 ml) was heated at reflux for 5 hours. Acetic acid (0.7ml) and sodium acetate (1.33 g) were added to the reaction mixture whichwas heated at reflux for a further 5 hours. The mixture was allowed tocool and the volatiles were removed by evaporation. The residue wasdissolved in water, adjusted to pH8 with 2M aqueous sodium hydroxidesolution and purified on a Diaion (trademark of Mitsubishi) HP20SS resincolumn eluting with methanol (gradient 0–50%) in water. The fractionscontaining product were concentrated by evaporation and then freezedried to give4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.55 g,83%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.9(m, 2H); 2.0–2.1(m, 2H);2.2–2.3(m, 2H); 3.05(m, 2H); 3.34(t, 2H); 3.6–3.7(br s, 2H); 3.94(s,3H); 4.27(t, 2H); 7.31(s, 1H); 7.55(s, 1H); 9.02(s, 1H)

A mixture of4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7 g, 5mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was heated atreflux for 3 hours. Excess thionyl chloride was removed by evaporationand by azeotroping with toluene (×2). The residue was suspended in etherand 10% aqueous solution of sodium hydrogen carbonate was added to themixture. The organic layer was separated, dried (MgSO₄) and the solventremoved by evaporation to give4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94 g,quantitative).

¹H NMR Spectrum: (CDCl₃) 1.8(br s, 4H); 2.17(m, 2H); 2.6(br s, 4H);2.7(t, 2H); 4.05(s, 3H); 4.3(t, 2H); 7.35(s, 1H); 7.38(s, 1H); 8.86(s,1H)

MS-ESI: 322 [MH]⁺

EXAMPLE 10

A suspension of4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74mg, 0.23 mmol), potassium carbonate (48 mg, 0.35 mmol) and7-hydroxyquinoline (40.6 mg, 0.28 mmol) in DMF (1.5 ml) was heated at100° C. for 3 hours. After cooling, the mixture was stirred for 10 hoursat ambient temperature and then overnight at 5° C. After dilution withmethylene chloride (5 ml), the mixture was poured onto a column ofsilica and was eluted with an increasing gradient of methanol/methylenechloride (10/90, 20/80) followed by ammonia/methanol (5%) in methylenechloride (25/75) to give, after removal of the volatiles by evaporationand drying under vacuum,6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline(82 mg, 88%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.751.9(m, 3H); 1.9–2.05(m,2H); 2.12(s, 3H); 2.8–2.9(d, 2H); 4.5(s, 3H); 4.1(d, 2H); 7.4(s, 1H);7.6(dd, 1H); 7.62(dd, 1H)

MS (ESI): 431 [MH]⁺

The starting material was prepared as follows:

To a solution of ethyl 4-piperidinecarboxylate (30 g, 0.19 mol) in ethylacetate (150 ml) cooled at 5° C. was added dropwise a solution ofdi-tert-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml)while maintaining the temperature in the range 0–5° C. After stirringfor 48 hours at ambient temperature, the mixture was poured onto water(300 ml). The organic layer was separated, washed successively withwater (200 ml), 0.1M aqueous hydrochloric acid (200 ml), saturatedsodium hydrogen carbonate (200 ml) and brine (200 ml); dried (MgSO₄) andevaporated to give ethyl4-(1-tert-butyloxycarbonylpiperidine)carboxylate (48 g, 98%).

¹H NMR Spectrum: (CDCl₃) 1.25(t, 3H); 1.45(s, 9H); 1.55–1.70(m, 2H);1.8–2.0(d, 2H); 2.352.5(m, 1H); 2.7–2.95(t, 2H); 3.9–4.1(br s, 2H); 4.15(q, 2H)

To a solution of ethyl 4-(1-tert-butyloxycarbonylpiperidine)carboxylate(48 g, 0.19 mol) in dry THF (180 ml) cooled at 0° C. was added dropwisea solution of 1M lithium aluminium hydride in THF (133 ml, 0.133 mol).After stirring at 0° C. for 2 hours, water (30 ml) was added followed by2M sodium hydroxide (10 ml). The precipitate was filtered throughdiatomaceous earth and washed with ethyl acetate. The filtrate waswashed with water, brine, dried (MgSO₄) and evaporated to give4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (36.3 g, 89%).

¹H NMR Spectrum: (CDCl₃) 1.05–1.2(m, 2H); 1.35–1.55(m, 10H); 1.6–1.8(m,2H); 2.6–2.8(t, 2H); 3.4–3.6(t, 2H); 4.0–4.2(br s, 2H)

MS (EI): 215 μM.]⁺

To a solution of 4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5g, 0.244 mol) in tert-butyl methyl ether (525 ml) was added1,4-diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol). After stirring for 15minutes at ambient temperature, the mixture was cooled to 5° C. and asolution of toluene sulphonyl chloride (62.8 g, 0.33 mmol) in tert-butylmethyl ether (525 ml) was added dropwise over 2 hours while maintainingthe temperature at 0° C. After stirring for 1 hour at ambienttemperature, petroleum ether (11) was added. The precipitate was removedby filtration. The filtrate was evaporated to give a solid. The solidwas dissolved in ether and washed successively with 0.5M aqueoushydrochloric acid (2×500 ml), water, saturated sodium hydrogen carbonateand brine, dried (MgSO₄) and evaporated to give4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine(76.7 g, 85%).

¹H NMR Spectrum: (CDCl₃) 1.0–1.2(m, 2H); 1.45(s, 9H); 1.65(d, 2H);1.75–1.9(m, 2H); 2.45(s, 3H); 2.55–2.75(m, 2H); 3.85(d, 1H); ⁴0.04.2(brs, 2H); 7.35(d, 2H); 7.8(d, 2H)

MS (ESI): 392 [MNa]⁺

To a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6 g, 0.1 mol)and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml) was added4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine(40 g, 0.11 mol). After stirring at 95° C. for 2.5 hours, the mixturewas cooled to ambient temperature and partitioned between water andethyl acetate/ether. The organic layer was washed with water, brine,dried (MgSO₄) and evaporated. The resulting oil was crystallised frompetroleum ether and the suspension was stored overnight (at 5° C.). Thesolid was collected by filtration, washed with petroleum ether and driedunder vacuum to give ethyl3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35g, 89%).

m.p. 81–83° C.

¹H NMR Spectrum: (CDCl₃) 1.2–1.35(m, 2H); 1.4(t, 3H); 1.48(s, 9H);1.8–1.9(d, 2H); 2.02.15(m, 2H); 2.75(t, 2H); 3.9(d, 2H); 3.95(s, 3H);4.05–4.25(br s, 2H); 4.35(q, 2H); 6.85(d, 1H); 7.55(s, 1H); 7.65(d, 1H)

MS (ESI): 416 [MNa]⁺

Elemental analysis: Found C 63.4 H 8.0 N 3.5 C₂₁H₃₁NO₆ 0.3H₂O Requires C63.2 H 8.0 N 3.5%

To a solution of ethyl3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35g, 89 mmol) in formic acid (35 ml) was added formaldehyde (12M, 37% inwater, 35 ml, 420 mmol). After stirring at 95° C. for 3 hours, thevolatiles were removed by evaporation. The residue was dissolved inmethylene chloride and 3M hydrogen chloride in ether (40 ml, 120 mmol)was added. After dilution with ether, the mixture was triturated until asolid was formed. The solid was collected by filtration, washed withether and dried under vacuum overnight at 50° C. to give ethyl3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, quant.).

¹H NMR Spectrum: (DMSOd₆) 1.29(t, 3H); 1.5–1.7(m, 2H); 1.95(d, 2H);2.0–2.15(br s, 1H); 2.72(s, 3H); 2.9–3.1(m, 2H); 3.35–3.5(br s, 2H);3.85(s, 3H); 3.9–4.05(br s, 2H); 4.3(q, 2H); 7.1(d, 1H); 7.48(s, 1H);7.6(d, 1H)

MS (ESI): 308 [MH]⁺

A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate(30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0–5° C.TFA (37.5 ml) was added followed by the dropwise addition over 15minutes of a solution of fuming 24M nitric acid (7.42 ml, 178 mmol) inmethylene chloride (15 ml). After completion of the addition, thesolution was allowed to warm up and stirred at ambient temperature for 2hours. The volatiles were removed under vacuum and the residue wasdissolved in methylene chloride (50 ml). The solution was cooled to 0–5°C. and ether was added. The precipitate was collected by filtration, anddried under vacuum at 50° C. The solid was dissolved in methylenechloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was addedfollowed by ether (500 ml). The solid was collected by filtration anddried under vacuum at 50° C. to give ethyl3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g,82%).

¹H NMR Spectrum: (DMSOd₆) 1.3(t, 3H); 1.45–1.65(m, 2H); 1.75–2.1 (m,3H); 2.75(s, 3H); 2.9–3.05(m, 2H); 3.4–3.5(d, 2H); 3.95(s, 3H); 4.05(d,2H); 4.3(q, 2H); 7.32(s, 1H); 7.66(s, 1H)

MS (ESI): 353 [MH]⁺

A suspension of ethyl3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g, 10mmol) in methanol (80 ml) containing 10% platinum on activated carbon(50% wet) (389 mg) was hydrogenated at 1.8 atmospheres pressure untiluptake of hydrogen ceased. The mixture was filtered and the filtrate wasevaporated. The residue was dissolved in water (30 ml) and adjusted topH10 with a saturated solution of sodium hydrogen carbonate. The mixturewas diluted with ethyl acetate/ether (1/1) and the organic layer wasseparated. The aqueous layer was further extracted with ethylacetate/ether and the organic layers were combined. The organic layerswere washed with water, brine, dried (MgSO₄), filtered and evaporated.The resulting solid was triturated in a mixture of ether/petroleumether, filtered, washed with petroleum ether and dried under vacuum at60° C. to give ethyl6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58 g,80%).

m.p. 111–112° C.

¹H NMR Spectrum: (CDCl₃) 1.35(t, 3H); 1.4–1.5(m, 2H); 1.85(m, 3H);1.95(t, 2H); 2.29(s, 3H); 2.9(d, 2H); 3.8(s, 3H); 3.85(d, 2H); 4.3(q,2H); 5.55(br s, 2H); 6.13(s, 1H); 7.33(s, 1H)

MS (ESI): 323 [MH]⁺

Elemental analysis: Found C 62.8 H 8.5 N 8.3 C₁₇H₂₆N₂O₄ 0.2H₂O RequiresC 62.6 H 8.2 N 8.6%

A solution of ethyl6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4g, 100 mmol) was added in portions every 30 minutes during 4 hours.Heating was prolonged for 30 minutes after the last addition. Aftercooling, the volatiles were removed under vacuum. The solid wasdissolved in ethanol (100 ml) and methylene chloride (50 ml). Theprecipitate was removed by filtration and the filtrate was concentratedto a final volume of 100 ml. The suspension was cooled to 5° C. and thesolid was collected by filtration, washed with cold ethanol followed byether and dried under vacuum overnight at 60° C. to give6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(12.7 g, 70%).

¹H NMR Spectrum: (DMSOd₆) 1.25–1.4(m, 2H); 1.75(d, 2H); 1.9(t, 1H);1.9(s, 3H); 2.16(s, 2H); 2.8(d, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s,1H); 7.44(s, 1H); 7.97(s, 1H)

MS (ESI): 304 [MH]⁺

A solution of6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing DMF (2801 μl)was refluxed at 85° C. for 1 hour. After cooling, the volatiles wereremoved by evaporation. The precipitate was triturated with ether,filtered, washed with ether and dried under vacuum. The solid wasdissolved in methylene chloride and saturated aqueous sodium hydrogencarbonate was added. The organic layer was separated, washed with water,brine, dried (MgSO₄) and evaporated to give4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2.9g, 98%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.75–1.9(m, 3H); 2.0(t, 1H);2.25(s, 3H); 2.85(d, 2H); 4.02(s, 3H); 4.12(d, 2H); 7.41(s, 1H); 7.46(s,1H); 8.9(s, 1H)

MS (ESI): 322 [MH]⁺

EXAMPLE 11

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13g, 0.4 mmol), (prepared as described for the starting material inExample 10), was reacted with 5-hydroxy-2-methylindole (74 mg, 0.5 mol)to give6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(137 mg, 79%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.7–1.95(m, 5H); 2.15(s, 3H);2.4(s, 3H); 2.8(d, 2H); 3.98(s, 3H); 4.05(d, 2H); 6.14(s, 1H); 6.88(d,1H); 7.29(s, 1H); 7.32(d, 1H); 7.35(s, 1H); 7.6(s, 1H); 8.45(s, 1H)

MS (ESI): 433 [MH]+

EXAMPLE 12

To a solution of4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline(115 mg, 0.28 mmol) and 7-hydroxyquinoline (50 mg, 0.33 mmol) in DMF(1.5 ml) was added potassium carbonate (60 mg, 0.42 mmol). The mixturewas stirred for 2 hours at 100° C. After cooling, and removal of thevolatiles by evaporation, the residue was partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with ethylacetate/methylene chloride/methanol(1/1/0 followed by 40/50/10 and 0/9/1). After removal of the volatilesby evaporation, the residue was triturated with pentane, filtered anddried under vacuum to give6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline(110 mg, 76%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.75–1.9(m, 3H); 2.05(t, 2H);2.72(t, 2H); 2.95(d, 2H); 3.05(s, 3H); 3.35–3.45(m, 2H); 4.00(s, 3H);4.1(d, 2H); 7.41(s, 1H); 7.57(dd, 1H); 7.62(dd, 1H); 7.65(s, 1H);7.93(s, 1H); 8.12(d, 1H); 8.45(d, 1H); 8.55(s, 1H); 8.95(d, 1H)

MS (ESI): 523 [MH]⁺

Elemental analysis: Found C 61.3 H 6.0 N 10.6 C₂₇H₃₀N₄O₅S 0.4H₂ORequires C 61.2 H 5.9 N 10.6%

The starting material was prepared as follows:

Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) wasadded in portions over 20 minutes to a solution of7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol),(prepared as described for the starting material in Example 1), in DMF(70 ml) and the mixture was stirred for 1.5 hours. Chloromethyl pivalate(5.65 g, 37.5 mmol) was added dropwise and the mixture stirred for 2hours at ambient temperature. The mixture was diluted with ethyl acetate(100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4ml). The organic layer was separated and the aqueous layer extractedwith ethyl acetate, the combined extracts were washed with brine, dried(MgSO₄) and the solvent removed by evaporation. The residue wastriturated with a mixture of ether and petroleum ether, the solid wascollected by filtration and dried under vacuum to give7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(10 g, 84%).

¹H NMR Spectrum: (DMSOd₆) 1.11(s, 9H); 3.89(s, 3H); 5.3(s, 2H); 5.9(s,2H); 7.27(s, 1H); 7.35(m, 1H); 7.47(t, 2H); 7.49(d, 2H); 7.51(s, 1H);8.34(s, 1H)

A mixture of7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(7 g, 17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg) inethyl acetate (250 ml), DMF (50 ml), methanol (50 ml) and acetic acid(0.7 ml) was stirred under hydrogen at atmospheric pressure for 40minutes. The catalyst was removed by filtration and the solvent removedfrom the filtrate by evaporation. The residue was triturated with ether,collected by filtration and dried under vacuum to give7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(4.36 g, 80%).

¹H NMR Spectrum: (DMSOd₆) 1.1(s, 9H); 3.89(s, 3H); 5.89(s, 2H); 7.0(s,1H); 7.48(s, 1H); 8.5(s, 1H)

A suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(6.12 g, 20 mmol) potassium carbonate (5.52 g, 40 mmol) in DMF (60 ml)was stirred at ambient temperature for 30 minutes.4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine(8.86 g, 24 mmol), (prepared as described for the starting material inExample 10), was added and the mixture was stirred at 100° C. for 2hours. After cooling, the mixture was poured onto water/ice (400 ml,1/1) containing 2M hydrochloric acid (10 ml). The precipitate wascollected by filtration, washed with water and dried under vacuum overphophorus pentoxide. The solid was triturated in a mixture ofether/pentane (1/1), collected by filtration and dried to give6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(7.9 g, 78.5%).

¹H NMR Spectrum: (DMSOd₆) 1.1 (s, 9H); 1.1–1.3(m, 2H); 1.42(s, 9H);1.73(d, 2H); 1.932.1(br s, 1H); 2.65–2.9(br s, 2H); 3.9(s, 3H);3.9–4.1(m, 4H); 5.9(s, 2H); 7.2(s, 1H); 7.5(s, 1H); 8.35(s, 1H)

MS (ESI): 526 [MNa]+

A solution of6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(7.9 g, 16 mmol) in methylene chloride (80 ml) containing 5.5M hydrogenchloride in isopropanol (80 ml) was stirred for 1 hour at ambienttemperature. Ether was added and the solid was collected by filtration,washed with ether and dried under vacuum at 60° C. to give6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-onehydrochloride (6.9 g, 100%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.15(s, 9H); 1.5–1.7(m, 2H); 2.0(d,2H); 2.2–2.3(br s, 1H); 3.0(t, 2H); 3.4(d, 2H); 3.94(s, 3H); 4.15(d,2H); 5.97(s, 2H); 7.3(s, 1H); 7.6(s, 1H); 8.65(s, 1H)

MS (ESI): 404 [MH]⁺

To a solution of6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-onehydrochloride (0.88 g, 2 mmol) and triethylamine (0.3 ml, 2.1 mmol) inmethanol (10 ml) and methylene chloride (10 ml) was added potassiumcarbonate (280 mg, 2 mmol) and methyl vinyl sulfone (0.4 ml, 2.1 mmol).After stirring for 2 hours at ambient temperature, the volatiles wereremoved under vacuum. The residue was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried (MgSO₄) andevaporated to give6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(0.55 g, 54%).

¹H NMR Spectrum: (DMSOd₆) 1.09(s, 9H); 1.25–1.4(m, 2H); 1.7–1.9(m, 3H);2.0(t, 2H); 2.7(t, 2H); 2.95(d, 2H); 3.02(s, 3H); 3.25–3.45(m, 2H);3.9(s, 3H); 4.0(d, 2H); 5.9(s, 2H); 7.15(s, 1H); 7.49(s, 1H); 8.35(s,1H)

MS (ESI): 510 [MH]^(+.)

To a suspension of6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(90 mg, 0.18 mmol) in methanol (3 ml) was added 2M aqueous sodiumhydroxide (180 μl, 0.35 mmol). After stirring for 2 hours at ambienttemperature, the mixture was adjusted to pH10 with 2M hydrochloric acid.The volatiles were removed under vacuum and the residue was suspended inwater, filtered, washed with water followed by ether and dried undervacuum at 60° C. to give6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(55 mg, 79%).

¹H NMR Spectrum: (DMSOd₆) 1.2–1.4(m, 2H); 1.7–1.85(m, 3H); 2.0(t, 2H);2.7(t, 2H); 2.9(d, 2H); 3.02(s, 3H); 3.3–3.5(m, 2H); 3.9(s, 3H); 4.0(d,2H); 7.11(s, 1H); 7.45(s, 1H); 7.97(s, 1H)

MS (ESI): 396 [MH]⁺

A solution of6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one(335 mg, 0.85 mmol) in thionyl chloride (5 ml) containing DMF (50 μl)was refluxed for 1 hour. After cooling, the volatiles were removed undervacuum and the residue was triturated with ether and filtered. The solidwas suspended in methylene chloride and sodium hydrogen carbonate wasadded. The organic layer was washed with water, brine, dried (MgSO₄) andevaporated. The residue was triturated with ether, filtered and driedunder vacuum to give4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline(335 mg, 95%).

¹H NMR Spectrum: (DMSOd₆) 1.25–1.45(m, 2H); 1.751.90(m, 3H); 2.0(t, 2H);2.7(t, 2H); 2.92(d, 2H); 3.03(s, 3H); 3.2–3.35(m, 2H); 4.0(s, 3H);4.1(d, 2H); 7.40(s, 1H); 7.45(s, 1H); 8.9(s, 1H)

MS (ESI): 414 [MH]⁺

EXAMPLE 13

Using a procedure analogous to that described for Example 10,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (130mg, 0.4 mmol), (prepared as described for the starting material inExample 10), was reacted with 4-methyl-7-hydroxyquinoline (80 mg, 0.5mol), (Chem. Ber. 1967, 100, 2077), to give6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline(160 mg, 90%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.7–1.95(m, 3H); 1.9(t, 2H);2.17(s, 3H); 2.74(s, 3H); 2.8(d, 2H); 4.07(s, 3H); 4.1(d, 2H); 7.4(m,2H); 7.65(dd, 1H); 7.65(s, 1H); 7.9(s, 1H); 8.21(d, 1H); 8.54(s, 1H);8.78(d, 1H)

MS (ESI): 445 [MH]⁺

EXAMPLE 14

A solution of4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline(115 mg, 0.28 mmol), (prepared as described for the starting material inExample 12), 5-hydroxy-2-methylindole (50 mg, 0.33 mmol) and potassiumcarbonate (60 mg, 0.42 mmol) in DMF (1.5 ml) was stirred at 100° C. for2 hours. After cooling, the mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried(MgSO₄) and evaporated. The residue was purified by chromatographyeluting with ethyl acetate/methylene chloride (1/1) followed bymethanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline(60 mg, 41%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H); 1.75–1.92(m, 3H); 2.02(t,2H); 2.4(s, 3H); 2.7(t, 2H); 2.95(d, 2H); 3.05(s, 3H); 4.0(s, 3H);4.05(d, 2H); 6.15(s, 1H); 6.85(dd, 1H); 7.25(s, 1H); 7.3(d, 1H); 7.38(s,1H); 7.6(s, 1H); 8.45(s, 1H)

MS (ESI): 525 [MH]⁺

Elemental analysis: Found C 60.7 H 6.2 N 10.5 C₂₇H₃₂O₅S 0.5H₂O RequiresC 60.8 H 6.2 N 10.5%

EXAMPLE 15

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g,0.4 mmol), (prepared as described for the starting material in Example9), was reacted with 7-hydroxy-4-methylquinoline (80 mg, 0.5 mol),(Chem. Berich. 1967, 100, 2077), to give6-methoxy-4-(4-methylquinolin-7yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(155 mg, 87%).

¹H NMR Spectrum: (DMSOd₆) 1.7(br s, 4H); 2.05(m, 2H); 2.5(br s, 4H);2.6(t, 2H); 2.75(s, 3H); 4.02(s, 3H); 4.3(t, 2H); 7.41(s, 1H); 7.45(d,1H); 7.65(s, 1H); 7.65(d, 1H); 7.95(s, 1H); 8.25(d, 1H); 8.55(s, 1H);8.8(d, 1H)

MS (ESI): 445 [MH]⁺

EXAMPLE 16

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g,0.4 mmol), (prepared as described for the starting material in Example9), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg,0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline(90 mg, 47%).

¹H NMR Spectrum: (DMSOd₆) 1.23(s, 6H); 1.7(br s, 4H); 1.85(s, 3H);2.0(m, 2H); 2.45(br s, 4H); 2.57(t, 2H); 3.95(s, 3H); 4.25(t, 2H);5.35(s, 1H); 5.9(s, 1H); 6.5(d, 1H); 6.8(dd, 1H); 6.85(s, 1H); 7.32(s,1H); 7.52(s, 1H); 8.5(s, 1H)

MS (ESI): 475 [MH]⁺

EXAMPLE 17

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13g, 0.4 mmol), (prepared as described for the starting material inExample 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol(95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), togive6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline(140 mg, 74%).

¹H NMR Spectrum: (DMSOd₆) 1.15(s, 6H); 1.3–1.45(m, 2H); 1.7–2.0(m, 8H);2.16(s, 3H); 2.65–2.85(d, 2H); 4.0(s, 3H); 4.05(d, 2H); 5.35(s, 1H);5.9(s, 1H); 6.5(d, 1H); 6.80(d, 1H); 6.82(s, 1H); 7.33(s, 1H); 7.5(s,1H); 8.52(s, 1H)

MS (ESI): 475 [MH]⁺

EXAMPLE 18

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13g, 0.4 mmol), (prepared as described for the starting material inExample 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline (87 mg,0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(61 mg, 33%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.7–1.95(m, 5H); 2.2(s, 3H);2.65(s, 3H); 2.7(s, 3H); 2.75–2.9(br d, 2H); 4.05(s, 3H); 4.1(d, 2H);7.3(s, 1H); 7.4(s, 1H); 7.52(d, 1H); 7.65(s, 1H); 7.8(s, 1H); 8.15(d,1H); 8.55(s, 1H)

MS (ESI): 459 [MH]⁺

EXAMPLE 19

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13g, 0.4 mmol), (prepared as described for the starting material inExample 10), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83mg, 0.5 mmol), (J. Chem. Soc. C, 1971, 2696), to give6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline(158 mg, 88%).

¹H NMR Spectrum: (DMSOd₆) 1.25–1.45(m, 2H); 1.8(d, 2H); 1.7–1.9(m, 1H);1.9(t, 2H); 2.2(s, 3H); 2.8(d, 2H); 3.97(s, 3H); 4.05(d, 2H); 4.65(s,2H); 6.8(s, 1H); 6.85(d, 1H); 7.05(d, 1H); 7.35(s, 1H); 7.52(s, 1H);8.55(s, 1H)

MS (ESI): 451 [MH]⁺

EXAMPLE 20

Using a procedure analogous to that described for Example 9,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g,0.4 mmol), (prepared as described for the (starting material in Example9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5mmol), (J. Chem. Soc. C, 1971, 2696), to give6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline(170 mg, 94%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 1.8–2.0(m, 2H); 2.0–2.15(m, 2H);2.2–2.35(m. 2H); 3.0–3.2(m, 2H); 3.4(t, 2H); 3.6–3.75(m, 2H); 4.05(s,3H); 4.35(t, 2H); 4.65(s, 2H); 6.85(s, 1H); 6.9(d, 1H); 7.1(d, 1H);7.5(s, 1H); 7.7(s, 1H); 8.9(s, 1H)

MS (ESI): 451 [MH]⁺

EXAMPLE 21

Using a procedure analogous to that described for Example 10,4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74mg, 0.23 mmol), (prepared as described for the starting material inExample 10), was reacted with 6-hydroxyquinoline (41 mg, 0.28 mol) togive6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline(89 mg, 94%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5(m, 2H); 1.8(d, 2H); 1.9(t, 2H);1.81.9(m, 1H); 2.2(s, 3H); 2.82(d, 2H); 4.02(s, 3H); 4.1(d, 2H); 7.4(s,1H); 7.6(dd, 1H); 7.65(s, 1H); 7.75(d, 1H); 7.95(s, 1H); 8.15(d, 1H);8.4(d, 1H); 8.55(s, 1H); 8.95(d, 1H)

MS (ESI): 431 [MH]⁺

EXAMPLE 22

To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250 mg, 0.74mmol), (prepared as described for the starting material in Example 1),in suspension in DMF (4 ml) were successively added4-chloro-7-hydroxyquinoline (133 mg, 0.74 mmol) and potassium carbonate(153 mg, 1 mmol) and the reaction mixture heated to 100° C. More4-chloro-7hydroxyquinoline (27 mg, 0.15 mmol) was added after one hourand heating was continued for a further 30 minutes. The productprecipitated upon cooling to ambient temperature. The reaction mixturewas diluted with water, the product was collected by filtration andwashed with more water. The dried solid was triturated with ether andfiltered to give4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(166 mg, 47%).

¹H NMR Spectrum: (DMSOd₆, CF₃CO₂D) 2.3(m, 2H); 3.2(m, 2H); 3.4(m, 2H);3.5(m, 2H); 3.7(m, 2H); 4.0(m, 2H); 4.1(s, 3H); 4.4(m, 2H); 7.55(s, 1H);7.75(s, 1H); 7.90(dd, 1H); 7.95(d, 1H); 8.15(d, 1H); 8.45 (d, 1H);8.80(s, 1H); 9.05(d, 1H)

MS-ESI: 481 [MH]⁺

Elemental analysis: Found C 61.8 H 5.1 N 11.5 C₂₅H₂₅ClN₄O₄ Requires C62.4 H 5.2 N 11.7%

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloroquinoline (17 g, 56 mmol), (Konishi etal. WO 96/11187), in TFA (170 ml) was heated at reflux for 2 hours. Thesolvent was removed under vacuum and the residue was triturated withether, filtered and washed with ether. The solid was suspended in anaqueous solution of sodium hydrogen carbonate (5.5 g, 65 mmol in 200 mlof water) and stirred at ambient temperature for 30 minutes. The solidwas collected by filtration, washed with water and dried overnight undervacuum and over phosphorus pentoxide to give 4-chloro-7-hydroxyquinoline(9.85 g, 98%).

¹H NMR Spectrum: (DMSOd₆) 7.37(s, 1H); 7.39(d, 1H); 7.62(d, 1H); 8.15(d,1H); 8.8(d, 1H)

MS-EI: m/z 179 [M.]+

EXAMPLE 23

A solution of4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74mg, 0.23 mmol), (prepared as described for the starting material inExample 10), and 2-hydroxynaphthalene (40 mg, 0.28 mmol) in DMF (1.5 ml)containing potassium carbonate (48 mg, 0.35 mmol) was stirred at 100° C.for 3.5 hours. After cooling, methylene chloride (4.5 ml) was added andthe mixture was poured onto a column of silica (SiO2 Isolute®) andeluted with, successively, methylene chloride, methylenechloride/methanol (9/1), methylene chloride/methanol/3M ammonia inmethanol (75/20/5). The fractions containing the product were evaporatedunder vacuum. The residues was triturated with ether, filtered and driedunder vacuum to give6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazoline(80 mg, 83%).

MS-ESI: 430 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H), 1.8 (d, 2H), 2.0 (t, 1H),2.2 (s, 3H). 2.85 (d, 2H), 3.3–3.4 (m, 2H), 4.02 (s, 3H), 4.1 (d, 2H),7.4 (s, 1H), 7.5 (dd, 1H), 7.55 (m, 2H), 7.65 (s, 1H), 7.88 (s, 1H),7.98 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H), 8.55 (s, 1H)

EXAMPLE 24

A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74mg, 0.23 mmol), (prepared as described for the starting material inExample 1), and 3,4-(methylenedioxy)aniline (53 mg, 0.24 mmol) in asolution of isopropanol (3.5 ml) containing 5.5M hydrogen chloride inisopropanol (42 μl) was heated for 3 hours. After cooling to ambienttemperature, the reaction mixture was cooled to 0° C. and maintained atthis temperature overnight. The precipitate was collected by filtration,washed with ethyl acetate and dried under vacuum to give4-(1,3-benzodioxol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(82 mg, 76%).

MS-ESI: 439 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.3–2.4 (m, 2H), 3.05–3.2 (m,2H), 3.25–3.35(m, 2H), 3.5 (d, 2H), 3.82 (t, 2H), 4.0 (d, 2H), 4.05 (s, 3H), 4.32 (t,2H), 6.1 (s, 2H), 7.02 (d, 1H), 7.1 (dd, 1H), 7.3 (s, 1H), 7.4 (s, 1H),8.32 (s, 1H), 8.8 (s, 1H)

EXAMPLES 25–29

Using an analogous procedure to that described in Example 24,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline, (prepared asdescribed for the starting material in Example 1), was used in thesynthesis of the compounds described in Table I hereinafter as detailedin the notes a)–e) to Table I.

TABLE I

Example Weight yield MS-ESI No. (mg) % [MH]+ note R 25 104 90 435.1 a1-H-indazol-6-yl 26 102 89 435.1 b 1-H-indazol-5-yl 27 99 84 452 c1,3-benzothiazol-6-yl 28 108 91 466 d 2-methyl-1,3- benzothiazol-5-yl 29102 95 435.1 e 2,3-dihydro-1H-inden-5-yl Notes a4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) wasreacted with 6-aminoindazole (32 mg) to give4-(1-H-indazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.2–3.3(m,2H), 3.52(d, 2H), 3.85(t, 2H), 4.0(d, 2H), 4.05(s, 3H), 4.32(t, 2H),7.42(s, 1H), 7.45(d, 1H), 7.85(d, 1H), 7.98(s, 1H), 8.1(s, 1H), 8.42(s,1H), 8.85(s, 1H) b 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline(74 mg) was reacted with 5-aminoindazole (32 mg) to give4-(1-H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.25–3.3(m,2H), 3.45–3.55(m, 2H), 3.8–3.9(m, 2H), 3.9–4.02(m, 2H), 4.05(s, 3H),4.32(t, 2H), 7.42(s, 1H), 7.65(m, 2H), 8.05(s, 1H), 8.15(s, 1H), 8.4(s,1H), 8.75(s, 1H) c 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline(74 mg) was reacted with 6-aminothiazole (36 mg) to give4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.3–2.4(m, 2H), 3.05–3.2(m, 2H), 3.2–3.3(m,2H), 3.55(d, 2H), 3.8(t, 2H), 4.0(d, 2H), 4.08(s, 3H), 4.32(t, 2H),7.4(s, 1H), 7.88(dd, 1H), 8.2(d, 1H), 8.4(s, 1H), 8.55(s, 1H), 8.85(s,1H), 9.42(s, 1H) d 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline(74 mg) was reacted with 6-amino-2-methylthiazole (57 mg) to give6-methoxy-4-(2-methyl-1,3-benzothiazol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.3–2.4(m, 2H), 2.85(s, 3H), 3.05–3.2(m, 2H),3.3(t, 2H), 3.4–3.5(m, 2H), 3.85(t, 2H), 4.0(d, 2H), 4.05(s, 3H),4.35(t, 2H), 7.42(s, 1H), 7.75(dd, 1H), 8.15(d, 1H), 8.3(s, 1H), 8.42(s,1H), 8.85(s, 1H) e 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline(74 mg) was reacted with 5-aminoindan (32 mg) to give4-(2,3-dihydro-1H-inden-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.08(m, 2H), 2.3–2.4(m, 2H), 2.9(m, 4H),3.05–3.2(m, 2H), 3.2–3.3(m, 2H), 3.5(d, 2H), 3.82(t, 2H), 4.0(d, 2H),4.05(s, 3H), 4.3(t, 2H), 7.32(d, 1H), 7.4(m, 2H), 7.55(s, 1H), 8.32(s,1H), 8.8(s, 1H)

EXAMPLE 30

A suspension of4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (130 mg,0.4 mmol), (prepared as described for the starting material in Example10), 7-hydroxy-2-methylchromone (88 mg, 0.5 mmol), (Bull Soc. Chim. Fr.1995, 132, 233), and potassium carbonate (83 mg, 0.6 mmol) was heated at100° C. for 1.5 hours. After cooling, the mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withwater, brine, dried (MgSO₄), and the volatiles were removed byevaporation. The residue was triturated with ether, collected byfiltration, washed with ether and dried under vacuum to give6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(170 mg, 92%).

MS-ESI: 462 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.75–1.95 (m, 5H); 2.2 (s,3H), 2.42 (s, 3H); 4.0 (s, 3H); 4.1 (d, 2H); 6.3 (s, 2H); 7.4 (s, 1H);7.45 (dd, 1H); 7.6 (s, 1H); 7.7 (s, 1H); 8.15 (d, 1H); 8.61 (s, 1H)

EXAMPLES 31–33

Using an analogous procedure to that described in Example 30, thecompounds described in Table II hereinafter and detailed in the notesa)–c) to Table II, were made.

TABLE II

Example Weight yield MS-ESI No. (mg) % [MH]⁺ note Q R 31 180 85 451 a1-methylpiperidin- 4-methyl-3,4-dihydro-2H- 4-ylmethoxy1,4-benzoxazin-6-yloxy 32 160 87 462 b 3-pyrrolidin-1-2-methyl-4-oxo-4H- ylpropoxy chromen-7-yloxy 33 100 56 451 c3-pyrrolidin-1- 4-methyl-3,4-dihydro-2H- ylpropoxy1,4-benzoxazin-6-yloxy a4-Chloro-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline (130 mg),(prepared as described for the starting material in Example 10), wasreacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol (83 mg), (J.Org. Chem. 1971, 36 (1)), to give6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(1-methylpiperidin-4-ylmethoxy)quinazoline¹H NMR Spectrum: (DMSOd₆) 1.6–1.75(m, 2H); 1.9–2.3(m, 5H); 2.8(s, 3H);2.9(s, 3H); 3.0–3.15(m, 2H); 3.3(br s, 2H); 3.5–3.6(d, 2H); 4.1(s, 3H);4.2(d, 2H); 4.3(t, 2H); 6.55(m, 1H); 6.75(s, 1H); 6.8(d, 1H); 7.6(s,1H); 7.75(s, 1H); 9.15(s, 1H) b4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130 mg),(prepared as described for the starting material in Example 9), wasreacted with 7-hydroxy-2-methylchromone (88 mg), (Bull Soc. Chim Fr.1995, 132, 233). After cooling, water was added (20 ml) and theprecipitate was collected by filtration and dried under vacuum overphosphorus pentoxide at 60° C. to give6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.8–2.0(m, 2H); 2.0–2.15(m, 2H);2.2–2.3(m, 2H); 2.4(s, 3H); 3.05–3.15(m, 2H); 3.3–3.4(m, 2H); 3.6–3.7(m,2H); 4.05(s, 3H); 4.35 (t, 2H); 6.3(s, 1H); 7.45(d, 1H); 7.5(s, 1H);7.65(s, 1H); 7.72(s, 1H); 8.15(d, 1H); 8.75(s, 1H) c4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130 mg),(prepared as described for the starting material in Example 9), wasreacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol (83 mg), (J.Org. Chem. 1971, 36 (1)), to give6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.85–2.0(m, 2H); 2.0–2.15(m, 2H); 2.25–2.35(m,2H); 2.83(s, 3H); 3.05–3.15(m, 2H); 3.3(t, 2H); 3.4(t, 2H); 3.7(br m,2H); 4.1(s, 3H); 4.3(t, 2H); 4.4(t, 2H); 6.52(d, 1H); 6.7(s, 1H); 6.8(d,1H); 7.55(s, 1H); 7.75(s, 1H); 9.1(s, 1H)

EXAMPLE 34

A solution of4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg,0.34 mmol), (prepared as described for the starting material in Example10), and 5-hydroxyindole (55 mg, 0.41 mmol) in DMF (1.5 ml) containingpotassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2hours. After cooling, water was added and the precipitate was collectedby filtration, washed with water followed by ether, and dried undervacuum over phosphorus pentoxide to give4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(90 mg, 64%).

MS-ESI: 419 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.35–1.5 (m, 2H); 1.8 (d, 2H); 1.95 (t, 2H);1.7–2.0 (m, 1H); 2.2 (s, 3H); 2.85 (d, 2H); 4.02 (s, 3H); 4.1 (d, 2H);6.45 (s, 1H); 7.0 (d, 1H); 7.35 (s, 1H); 7.4–7.5 (m, 3H); 7.6 (s, 1H);8.5 (s, 1H)

Elemental analysis: Found C 67.4 H 6.5 N 13.1 C₂₄H₂₆N₄O₃ 0.5H₂O RequiresC 67.4 H 6.4 N 13.1%

EXAMPLE 35

Using an analogous procedure to that described in Example 34,4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg,0.34 mmol), (prepared as described for the starting material in Example10), was reacted with 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol),(Arch. Pharm. 1972, 305, 159). The crude product was purified by columnchromatography eluting with methanol/methylene chloride (1/9) followedby 3M ammonia in methanol/methanol/methylene chloride (5/15/80) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(60 mg, 40%).

MS-ESI: 447 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.2–1.4 (m, 2H); 1.7 (d, 2H); 1.8 (t, 2H);1.7–1.9 (m, 1H); 2.05 (s, 3H); 2.12 (s, 3H); 2.25 (s, 3H); 2.75 (d, 2H);3.9 (s, 3H); 4.0 (d, 2H); 6.8 (d, 1H); 7.15 (s, 1H); 7.2 (d, 1H); 7.3(s, 1H); 7.52 (s, 1H); 8.45 (s, 1H)

Elemental analysis: Found C 68.6 H 6.9 N 12.5 C₂₆H₃₀N₄O₃ 0.4H₂O RequiresC 68.8 H 6.8 N 12.4%

EXAMPLE 36

Using an analogous procedure to that described in Example 34,4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (10 mg, 0.34mmol), (prepared as described for the starting material in Example 9),was reacted with 5-hydroxyindole (55 mg, 0.41 mmol). The crude productwas purified by chromatography on alumina, eluting with methanol/ethylacetate/methylene chloride (5/45/50) to give4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (70mg, 50%).

MS-ESI 419 [MH]+

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.9–2.0 (m, 2H); 2.1 (m, 2H); 2.3 (t,2H); 3.0–3.15 (m, 2H); 3.4 (t, 2H); 3.6–3.75 (m, 2H); 4.1 (s, 3H); 4.4(t, 2H); 6.5 (s, 1H); 7.05 (d, 1H); 7.5 (s, 1H); 7.5–7.6 (m, 2H); 7.85(s, 1H); 9.11 (s, 1H)

Elemental analysis: Found C 63.7 H 6.4 N 12.1 C₂₄H₂₆N₄O₃ 1.9H₂O RequiresC 63.7 H 6.6 N 12.4%

EXAMPLE 37

A suspension of4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg,0.31 mmol), (prepared as described for the starting material in Example10), and 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) in isopropanol (6ml) containing 5.5M hydrogen choride in isopropanol (60 μL) was heatedfor 30 minutes at 70° C. After cooling, the solid was collected byfiltration, washed with isopropanol, followed by ether and dried undervacuum to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolinehydrochloride (118 mg, 74%).

MS-ESI: 446 [MH]+

¹H NMR Spectrum: (DMSOd₆): 1.8–1.9 (m, 2H); 2.0 (d, 2H); 2.1–2.2 (m,1H); 2.16 (s, 3H); 2.33 (s, 3H); 2.75 (br s, 3H); 2.95–3.05 (m, 2H); 3.5(d, 2H); 4.0 (s, 3H); 4.07 (d, 2H); 7.25 (d, 1H); 7.4 (d, 1H); 7.42 (s,1H); 7.52 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H); 10.0 (br s, 1H); 10.9 (s,1H); 11.25 (br s, 1H)

Elemental analysis: Found C 58.5 H 6.8 N 12.9 C₂₆H₃₁N₅O₂ 1H₂O 1.9HClRequires C 58.6 H 6.6 N 13.1%

EXAMPLE 38

Using an analogous procedure to that described in Example 37,4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31mmol), (prepared as described for the starting material in Example 9),was reacted with 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) to give4(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolinehydrochloride (114 mg, 72%).

MS-ESI: 446 [MH]+

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.85–2.0 (m, 2H); 2.05–2.15 (m, 2H);2.1 (s, 3H);

-   -   2.2 (s, 3H); 2.25–2.35 (m, 2H); 2.35 (s, 3H); 3.0–3.15 (m, 2H);        3.32–3.42 (m, 2H); 3.6–3.7 (m, 2H); 4.05 (s, 3H); 4.3 (t, 2H);        7.2 (d, 1H); 7.3 (s, 1H); 7.35 (d, 1H); 7.57 (s, 1H); 8.2 (s,        1H); 8.8 (s, 1H)

Elemental analysis: Found C 58.8 H 7.0 N 12.5 C₂₆H₃₁N₅O 1.9H₂O 1.9HClRequires C 58.6 H 7.1 N 12.9% 0.1isopropanol

EXAMPLE 39

Using an analogous procedure to that described in Example 38,4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31mmol), (prepared as described for the starting material in Example 9),was reacted with 5-amino-2-methylindole (50 mg, 0.34 mmol) to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazolinehydrochloride (138 mg, 89%).

MS-ESI: 432 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.8–1.9 (m, 2H); 2.0–2.1 (m, 2H); 2.15–2.35(m, 2H); 2.4 (s, 3H); 3.0–3.1 (m, 2H); 3.2–3.3 (m, 2H); 3.5–3.6 (m, 2H);4.0 (s, 3H); 4.32 (t, 2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.3 (m, 2H); 7.65(s, 1H); 8.25 (s, 1H); 8.75 (s, 1H); 10.75 (br s, 1H); 11.15 (s, 1H);11.25 (br s, 1H)

Elemental analysis: Found C 58.9 H 6.6 N 13.5 C₂₅H₂₉N₅O₂ 2.2HCl RequiresC 58.7 H 6.2 N 13.5% 0.1isopropanol

EXAMPLE 40

A mixture of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(100 mg, 0.31 mmol), (prepared as described for the starting material inExample 9), and 7-hydroxy-2,4-dimethylquinoline (64 mg, 0.36 mmol),(Chem. Berichte, 1903, 36, 4016), in DMF (3 ml) containing potassiumcarbonate (86 mg, 0.62 mmol) was heated at 90° C. for 3 hours. Aftercooling, the mixture was poured onto a column of silica and eluted with2.5M ammonia in methanol/methylene chloride (5/95) to give4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(50 mg, 35%).

MS-ESI: 459 [MH]+

¹H NMR Spectrum: (CDCl₃) 1.8 (br s, 4H); 2.2 (m, 4H); 2.55 (br s, 4H);2.7 (2s, 6H); 2.68 (m, 2H); 4.05 (s, 3H); 4.3 (t, 2H); 7.15 (s, 1H);7.35 (s, 1H); 7.45 (d, 1H); 7.6 (s, 1H); 7.9 (s, 1H); 8.05 (d, 1H); 8.6(s, 1H)

Elemental analysis: Found C 70.4 H 7.1 N 12.1 C₂₇H₃₀N₄O₃ 0.2etherRequires C 70.5 H 6.8 N 11.8%

EXAMPLE 41

Using an analogous procedure to that described in Example 37,4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg,0.155 mmol), (prepared as described for the starting material in Example10), was reacted with 5-amino-2-methylindole (0.171 mmol) to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(1-methylpiperidin4-ylmethoxy)quinazoline hydrochloride (72 mg, quant.).

MS-ESI: 432 [MH]+

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.5–1.7 (m, 2H); 2.05 (d, 2H);2.1–2.2 (m, 1H); 2.45 (s, 3H); 2.8 (s, 3H); 3.05 (t, 2H); 3.5 (d, 2H);4.0 (s, 3H); 4.1 (d, 2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.32 (d, 1H); 7.4(d, 1H); 7.6 (s, 1H); 8.2 (s, 1H); 8.85 (s, 1H)

Elemental analysis: Found C 53.9 H 6.8 N 12.4 C₂₅H₂₉N₅O₂ 2.6H₂O 2.07HClRequires C 54.2 H 6.6 N 12.6%

EXAMPLE 42

A suspension of4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31mmol), (prepared as described for the starting material in Example 9),and 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998,41, 4062), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62mmol) was heated at 90° C. for 2 hours. After cooling, the mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water, brine, dried and the volatiles wereremoved by evaporation. The residue was triturated with minimal ether,collected by filtration and dried under vacuum to give6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(95 mg, 69%).

MS-ESI: 445 [MH]+

¹H NMR Spectrum: (CDCl₃) 1.8 (br s, 4H); 2.2 (m, 2H); 2.5 (br s, 4H);2.7 (t, 2H); 2.8 (s, 3H); 4.1 (s, 3H); 4.3 (t, 2H); 7.3 (d, 1H); 7.35(s, 1H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.85 (d, 1H); 7.9 (s, 1H); 8.1 (d,1H); 8.6 (s, 1H)

EXAMPLE 43

Using an analogous procedure to that described in Example 42,4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline(156 mg, 0.38 mmol), (prepared as described for the starting material inExample 12), was reacted with 7-hydroxy-2-methylquinoline (66 mg, 0.4mmol), (J. Med. Chem. 1998, 41, 4062), to give6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline(166 mg, 82%).

MS-ESI: 537 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.75–1.95 (m, 3H); 1.95–2.15(m, 2H); 2.7 (s, 3H); 2.7–2.8 (m, 2H); 2.9–3.0 (m, 2H); 3.05 (s, 3H);3.2–3.35 (m, 2H), 4.02 (s, 3H); 4.1 (d, 2H); 7.4 (s, 1H); 7.45 (d, 1H);7.55 (d, 1H); 7.65 (s, 1H); 7.8 (s, 1H); 8.05 (d, 1H); 8.35 (d, 1H);8.55 (s, 1H)

Elemental analysis: Found C 62.2 H 6.3 N 10.4 C₂₈H₃₂N₄O₅S 0.35etherRequires C 62.4 H 6.4 N 10.2% 0.2DMF

EXAMPLE 44

A suspension of4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg,0.155 mmol), (prepared as described for the starting material in Example10), and 5-hydroxy-2-trifluoromethylindole (34 mg, 0.17 mmol) in DMF(1.5 ml) containing potassium carbonate (43 mg, 0.31 mmol) was heated at90° C. for 2 hours. After cooling, the mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withbrine, dried (MgSO₄) and the volatiles were removed by evaporation. Theresidue was purified by column chromatography eluting withmethanol/ethyl acetate/methylene chloride (10/50/40) followed by 2.5Mammonia in methanol/ethyl acetate/methylene chloride (10/50/40) to give6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5yloxy)quinazoline(35 mg, 48%).

MS-ESI: 487 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.25–1.4 (m, 2H); 1.75 (d, 2H); 1.8 (t, 2H);1.7–2.0 (m, 1H); 2.2 (s, 3H); 2.75 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H);7.0 (s, 1H); 7.25 (d, 1H); 7.4 (s, 1H); 7.6 (d, 1H); 7.8 (s, 1H); 8.5(s, 1H); 12.5 (s, 1H)

Elemental analysis: Found C 60.2 H 5.8 N 10.9 C₂₅H₂₅F₃N₄O₃ 0.7H₂O0.2ether Requires C 60.3 H 5.6 N 10.9%

The starting material was prepared as follows:

A solution of (4-methoxy-2-methylphenyl)-carbamic acid-1,1-dimethylethylester (2 g, 8.43 mmol), (J. Med. Chem. 1996, 39,5119), in dry THF (25ml) was cooled to −40° C. and sec-butyllithium (15 ml, 19.5 mmol) wasadded. After stirring for 15 minutes at this temperature,N-methyl-N-methoxytrifluoroacetamide (1.32 g, 8.43 mmol) in THF (20 ml)was added in portions. Stirring was continued for 1 hour at −40° C. andthen the mixture was allowed to warm to ambient temperature. The mixturewas poured onto ether/1M hydrochloric acid. The organic layer wasseparated, washed with water, brine, dried (MgSO₄) and the volatileswere removed by evaporation.

The crude residue (1.4 g) was dissolved in methylene chloride (8 ml) andTFA was added (1.5 ml). After stirring for 3 hours at ambienttemperature, the volatiles were removed under vacuum. The crude productwas partitoned between methylene chloride and water. The organic layerwas separated, washed with water, brine, dried (MgSO₄) and the volatileswere removed by evaporation. The residue was purified by columnchromatography, eluting with ether/petroleum ether (1/9) to give5-methoxy-2-trifluoromethylindole (845 mg, 47% over 2 steps).

¹H NMR Spectrum: (CDCl₃) 3.83 (s, 3H), 6.82 (s, 1H), 7.0 (dd, 1H), 7.1(s, 1H), 7.3 (d, 1H), 8.15 (br s, 1H)

A solution of 5-methoxy-2-trifluoromethylindole (800 mg, 3.7 mmol) inmethylene chloride (6 ml) was cooled to −15° C. and a solution of 1Mboron tribromide in methylene chloride (7.44 ml, 7.4 mmol) was added inportions. The mixture was allowed to warm to ambient temperature and wasstirred for 45 minutes. After cooling to 0° C., saturated aqueous sodiumhydrogen carbonate (25 ml) was added. The mixture was extracted withethyl acetate. The organic layer was dried (MgSO₄) and the volatileswere removed by evaporation. The residue was purified by columnchromatography eluting with ethyl acetate/petroleum ether. After removalof the volatiles by evaporation, the solid was triturated with pentane,collected by filtration and dried under vacuum to give5-hydroxy-2-trifluoromethylindole (290 mg, 39%).

MS-EI: 201 μM.]+

¹H NMR Spectrum: (CDCl₃) 4.64 (s, 1H), 6.8 (s, 1H), 6.92 (dd, 1H), 7.1(s, 1H), 7.3 (d, 1H), 8.3 (br s, 1H)

Elemental analysis: Found C 53.3 H 2.9 N 6.8 C₉H₆F₃NO 0.1 H₂O Requires C53.3 H 3.1 N 6.9%

EXAMPLE 45

Using an analogous procedure to that described in Example 44,4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.3mmol), (prepared as described for the starting material in Example 9),was reacted with 5-hydroxy-2-trifluoromethylindole (75 mg, 0.37 mmol),(prepared as described for the starting material in Example 44), to give6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline(105 mg, 70%).

MS-ESI: 487 [MH]+

¹H NMR Spectrum: (CDCl₃) 1.8 (m, 4H); 2.1–2.3 (m, 2H); 2.55 (br s, 4H);2.7 (t, 2H); 4.1 (s, 3H); 4.3 (t, 2H); 6.95 (s, 1H); 7.2 (dd, 1H); 7.35(s, 1H); 7.5 (d, 1H); 7.55 (s, 1H); 7.6 (s, 1H); 8.6 (s, 1H); 8.8 (s,1H)

Elemental analysis: Found C 61.7 H 5.5 N 11.5 C₂₅H₂₅F₃N₄O₃ Requires C61.7 H 5.2 N 11.5%

EXAMPLE 46

Using an analogous procedure to that described in Example 42,4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg,0.31 mmol), (prepared as described for the starting material in Example10), was reacted with 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol),(J. Med. Chem. 1998, 41, 4062), to give6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline(86 mg, 63%).

MS-ESI: 445 [MH]+

¹H NMR Spectrum: (CDCl₃) 1.4–1.6 (m, 2H); 1.95 (d, 2H); 2.05 (t, 2H);1.9–2.1 (m, 1H); 2.35 (s, 3H); 2.8 (s, 3H); 2.95 (d, 2H); 4.1 (s, 3H);4.15 (d, 2H); 7.3 (m, 2H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.9 (d, 1H); 7.95(s, 1H); 8.1 (d, 1H); 8.6 (s, 1H)

Elemental analysis: Found C 69.7 H 6.5 N 12.8 C₂₆H₂₈N₄O₃ 0.2H₂O RequiresC 69.7 H 6.4 N 12.5%

EXAMPLE 47

A suspension of4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (10 mg, 0.34mmol), (prepared as described for the starting material in Example 9),and 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972,305, 159), in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51mmol) was heated at 100° C. for 2 hours. After cooling, the residue waspurified by chromatography, eluting with methanol/methylene chloride(1/9) followed by 2.5M ammonia in methanol/methanol/methylene chloride(5/10/85) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(50 mg, 33%).

MS-ESI: 447 [MH]+

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.9–2.0 (m, 2H); 2.05–2.15 (m, 2H);2.15 (s, 3H); 2.3–2.4 (m, 2H); 2.4 (s, 3H), 3.05–3.15 (m, 2H); 3.35–3.45(t, 2H); 3.7 (br s, 2H); 4.1 (s, 3H); 4.4 (t, 2H); 6.95 (d, 1H); 7.3 (s,1H); 7.35 (d, 1H); 7.55 (s, 1H); 7.85 (s, 1H); 9.15 (s, 1H)

Elemental analysis: Found C 67.7 H 6.8 N 12.2 C₂₆H₃₀N₄O₃ 0.8H₂O RequiresC 67.8 H 6.9 N 12.2%

EXAMPLE 48

Using an analogous procedure to that described in Example 32,7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared asdescribed for the starting material in Example 1), was reacted with5-hydroxy-2-methylindole (0.59 g, 4 mmol) to give7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.25 g,91%).

MS-ESI: 412 [MH]+

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 4.0 (s, 3H); 5.35 (s, 2H); 6.15(s, 1H); 6.85 (s, 1H); 7.2–7.6 (m, 9H); 8.5 (s, 1H)

Elemental analysis: Found C 72.2 H 5.1 N 10.2 C₂₅H₂₁N₃O₃ 0.2H₂O RequiresC 72.3 H 5.2 N 10.1%

The starting material may be prepared as follows:

A solution of boron tribromide (32.5 ml, 341 mmol) in methylene choride(60 ml) was added in portions to a solution of 5-methoxy-2-methylindole(25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. Afterstirring for 15 minutes at −30° C., the mixture was warmed up to ambienttemperature and stirred for 1 hour. Methylene chloride (300 ml) wasadded in portions and the mixture was cooled to 0° C. Water was added inportions and the mixture was adjusted to pH6 with 4N sodium hydroxide.The organic layer was separated. The aqueous layer was extracted withmethylene chloride and the organic layers were combined, washed withwater, brine, dried (MgSO₄) and the volatiles were removed byevaporation. The residue was purified by column chromatography elutingwith ethyl acetate/methylene chloride (1/9 followed by 15/85) to give5-hydroxy-2-methylindole (21.2 g, 93%).

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 5.95 (s, 1H); 6.5 (dd, 1H); 6.7(s, 1H); 7.05 (d, 1H); 8.5 (s, 1H)

EXAMPLE 49

A solution of 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(0.2 g, 0.5 mmol), (prepared as described in Example 48), in a mixtureof methylene chloride (5 ml) and DMF (2 ml) containing 10%palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8atmospheres pressure for 2 hours. The suspension was filtered and thecatalyst was washed with methanol followed by methylene chloride. Thevolatiles were removed from the filtrate by evaporation. The residue wastriturated with water. The resulting solid was washed with water anddried under vacuum over phosphorus pentoxide at 60° C. to give7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg, 89%).

MS-ESI: 322 [MH]+

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 4.0 (s, 3H); 6.15 (s, 1H); 6.9(d, 1H); 7.2 (s, 1H); 7.25 (s, 1H); 7.3 (d, 1H); 7.6 (s, 1H); 8.4 (s,1H)

EXAMPLE 50

A suspension of4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54 mmol),(prepared as described for the starting material in Example 44), in DMF(1.5 ml) containing potassium carbonate (94 mg, 0.67 mmol) was heated at100° C. for 1 hour. After cooling, the precipitate was collected byfiltration, washed with ether, and dried under vacuum to give6-methoxy-7-(3-methylsulphonylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline(195 mg, 87%).

MS-ESI: 496 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.25–2.4 (m, 2H), 3.1 (s, 3H), 3.35(t, 2H), 4.1 (s, 3H), 4.4 (t, 2H), 7.1 (s, 1H), 7.3 (d, 1H), 7.5 (s,1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.78 (s, 1H), 8.9 (s, 1H)

The starting material was prepared as follows:

A solution of 3-(methylthio)-1-propanol (5.3 g, 50 mmol) in methanol(500 ml) was added to a solution of OXONE, (trade mark of E.I. du Pontde Nemours & Co., Inc), (30 g) in water (150 ml) and the mixture stirredat ambient temperature for 24 hours. The precipitated solid was removedby filtration and the methanol removed from the filtrate by evaporation.The aqueous residue was saturated with sodium chloride and extractedwith methylene chloride (4×25 ml). The aqueous residue was thensaturated with ammonium chloride and extracted with ethyl acetate (4×25ml). The extracts were combined, dried (MgSO₄) and the solvent removedby evaporation to give 3-(methylsulphonyl)-1-propanol (610 mg, 9%) as anoil.

¹H NMR Spectrum: (CDCl₃) 2.10(m, 2H); 2.96(s, 3H); 3.20(t, 2H); 3.80(t,2H)

MS-ESI: 139 [MH]⁺

Alternatively the 3-(methylsulphonyl)-1-propanol may be prepared asfollows:

-   -   m-Chloroperoxybenzoic acid (67%, 25 g, 97.2 mmol) was added in        portions to 3-(methylthio)-1-propanol (5 ml, 48.6 mmol) in        solution in dichloromethane. Some m-chlorobenzoic acid        precipitated out and was removed by filtration. The filtrate was        evaporated and the residue was purified over alumina using first        dichloromethane (100%) then dichloromethane/methanol (95/5) to        give 3-(methylsulphonyl)-1-propanol (4.18 g, 62%) as an oil.

Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(6 g, 19.6 mmol), (prepared as described for the starting material inExample 12), in methylene chloride (150 ml). This was followed by theaddition of 3-(methylsulphonyl)-1-propanol (3.5 g, 25.4 mmol) anddiethyl azodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reactionwas complete once the reaction became homogeneous. Silica was added andthe volatiles were removed by evaporation. The free flowing powder wasplaced on the top of a flash chromatography column pre-equilibrated withethyl acetate (100%). Elution was done using ethyl acetate (100%)followed by methylene chloride/ethyl acetate/methanol (60/35/5). Thevolatiles were removed by evaporation to give6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(7.58 g, 91%) as a white solid.

¹H NMR Spectrum: (CDCl₃) 1.2(s, 9H); 2.4–2.5(m, 2H); 3.0(s, 3H);3.25–3.35(t, 2H); 5.95(s, 1H); 7.1(s, 1H); 7.65(s, 1H); 8.2(s, 1H)

6-Methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(7 g, 17 mmol) was suspended in methanol and 2M sodium hydroxide (3.3ml, 6.6 mmol) was added with continuous stirring. The reaction mixturebecame homogeneous after 15 minutes. After a further 45 minutes waterwas added (7 ml) and the reaction mixture was adjusted to pH10 with 2Mhydrochloric acid. The precipitate (a white solid) was collected byfiltration, washed with water and dried over phosphorus pentoxide undervacuum to give6-methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (5 g,90%).

¹H NMR Spectrum: (DMSOd₆) 2.2–2.3(m, 2H); 3.05(s, 3H); 3.35(t, 2H);3.9(s, 3H); 4.25(t, 2H); 7.15(s, 1H); 7.5(s, 1H); 8.0(s, 1H)

6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml)was added under argon and the mixture was heated at reflux for 1.5hours. The thionyl chloride was eliminated by several azeotropicdistillations using toluene. The solid residue was suspended inice/water and a saturated solution of sodium hydrogen carbonate wasadded to adjust the mixture to pH7. The solid was collected byfiltration, washed with water and dried in a vacuum dessicator overphosphorus pentoxide to give4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g,88%).

EXAMPLES 51–52

Using an analogous procedure to that described in Example 50,4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline, (prepared asdescribed for the starting material in Example 50), was reacted with theappropriate phenol to give the compounds described in Table III:

TABLE III

Example Weight Yield MS-ESI No. (mg) % [MH]⁺ Ar Note 51 189 92 4542-methylquinolin-7-yl a 52 175 90 428 indol-5-yl b a4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45mmol) was reacted with 7-hydroxy-2-methylquinoline (86.6 mg, 0.54 mmol),(J. Med. Chem. 1998, 41, 4062). After cooling, water was added and theprecipitate was collected by filtration, washed with water, followed byether and dried under vacuum to give6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-methylquinolin-7-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.2–2.35(m, 2H), 2.95(s, 3H), 3.1(s,3H), 3.35(m, 2H), 4.05(s, 3H), 4.4(t, 2H), 7.5(s, 1H), 7.7(s, 1H),7.95(dd, 1H), 8.02(d,; 1H), 8.2(s, 1H), 8.48(d, 1H), 8.7(s, 1H), 9.12(d,1H) b Using an analogous procedure to that described in note a,4-chloro-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline (150 mg,0.45 mmol) was reacted with 5-hydroxyindole (72.4 mg, 0.54 mmol) to give4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆) 2.2–2.35(m, 2H), 3.1(s, 3H), 3.3–3.4(t, 2H),4.0(s, 3H), 4.4(t, 2H), 6.5(s, 1H), 7.0(dd, 1H), 7.4(s, 1H), 7.4–7.5(m,3H), 7.6(s, 1H), 8.5(s, 1H), 11.25(s, 1H)

EXAMPLE 53

0.5M Triphenylphosphine in methylene chloride and diisopropylazodicarboxylate (150 μl, 0.75 mmol) were added in portions to asuspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(112 mg, 0.35 mmol), (prepared as described in Example 49), andN,N-dimethylethanolamine (62 mg, 0.7 mmol) in methylene chloride (2 ml).After stirring for 2 hours at ambient temperature, the reaction mixturewas poured onto an isolute® column (10 g of silica) and eluted withethyl acetate/methylene chloride (1/1) followed by methanol/ethylacetate/methylene chloride (10/40/50), methanol/methylene chloride(10/90), and 3M ammonia in methanol/methanol/methylene chloride(5/15/80). After removal of the volatiles by evaporation, the residuewas dissolved in the minimum amount of methylene chloride (about 3 ml)and ether and petroleum ether (about 10 ml) was added. The resultingprecipitate was collected by filtration and dried under vacuum to give7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(52 mg, 38%).

MS-ESI: 393 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.25 (s, 6H), 2.4 (s, 3H), 2.75 (t, 2H), 4.0(s, 3H), 4.3 (t, 2H), 6.15 (s, 1H), 6.87 (d, 1H), 7.25 (s, 1H), 7.3 (d,1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.5 (s, 1H)

EXAMPLES 54–56

Using an analogous procedure to that described in Example 53, theappropriate alcohols were reacted with7-hydroxy-6-methoxy-4(2-methylindol-5-yloxy)quinazoline, (prepared asdescribed in Example 49), in analogous proportions to give the compoundsdescribed in Table IV:

TABLE IV

Example Weight Yield MS-ESI No. (mg) % [MH]⁺ R Note 54  25 17 4192-pyrrolidin-1-ylethoxy a 55 112 74 433 1-methylpiperidin-3- b ylmethoxy56 115 72 456 2-(N-methyl-N-(4- c pyridyl)amino)ethoxy a7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 1-(2-hydroxyethyl)pyrrolidine (81 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.65–1.8(m, 4H), 2.4(s, 3H), 2.6(br s, 4H),2.9(t, 2H), 4.0(s, 3H), 4.3(t, 2H), 6.15(s, 1H), 6.9(d, 1H), 7.25(s,1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) b7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 1-methyl-3-piperidinemethanol (90 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.45–2.2(m, 7H), 2.18(s, 3H), 2.4(s, 3H),2.6(br d, 1H), 2.85(br d, 1H), 4.0(s, 3H), 4.1(d, 2H), 6.15(s, 1H),6.9(d, 1H), 7.25(d, 1H), 7.3(d, 1H), 7.35(s, 1H), 7.6(s, 1H), 8.5(s, 1H)c 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 2-(N-methyl-N-(4-pyridyl)amino)ethanol (106 mg), (EP 0359389), togive6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.4(s, 3H), 3.1(s, 3H), 3.9(t, 2H), 3.97(s,3H), 4.4(t, 2H), 6.15(s, 1H), 6.75(d, 2H), 6.87(dd, 1H), 7.25(s, 1H),7.3(d, 1H), 7.35(s, 1H), 7.6(s, 1H), 8.15(d, 2H), 8.5(s, 1H)

EXAMPLES 57–66

Using an analogous procedure to that described in Example 53, exceptthat ammonia in methanol was not necessary during the columnchromatography, the appropriate alcohols were reacted with7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared asdescribed in Example 49), in analogous proportions to give the compoundsdescribed in Table V:

TABLE V

Example Weight Yield MS-ESI No. (mg) % [MH]⁺ R Note 57 115 76 4352-morpholinoethoxy a 58 64 42 433 2-piperidinoethoxy b 59 66 43 4372-(N-(2-methoxyethyl)-N- c methylamino)ethoxy `60 118 75 4493-morpholinopropoxy d 61 101 68 424 2-(2-methoxyethoxy)ethoxy e 62 81 57407 3-(N,N-dimethylamino)- f propoxy 63 160 92 497 3-(1,1-dioxothiomor-g pholino)propoxy 64 121 83 417 2-(1H-1,2,4-triazol-1- h yl)ethoxy 65 3822 492 2-(2-(4-methylpiperazin-1- i yl)ethoxy)ethoxy 66 80 48 4792-(2-morpholinoethoxy)- j ethoxy a7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 4-(2-hydroxyethyl)morpholine (92 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.4(s, 3H), 2.5–2.7(m, 4H), 2.8(t, 2H), 3.6(t,4H), 4.0(s, 3H), 4.35(t, 2H), 6.15(s, 1H), 6.87(dd, 1H), 7.25(s, 1H),7.32(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) b7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 1-(2-hydroxyethyl)piperidine (90 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H), 1.4–1.6(m, 4H), 2.4(s, 3H),2.4–2.5(m, 4H), 2.75(t, 2H), 3.97(s, 3H), 4.3(t, 2H), 6.15(s, 1H),6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H)c 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (93 mg) to give6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.35(s, 3H), 2.4(s, 3H), 2.65(t, 2H), 2.85(t,2H), 3.25(s, 3H), 3.45(t, 2H), 3.97(s, 3H), 4.25(t, 2H), 6.15(s, 1H),6.9(dd, 1H), 7.25(s, 1H), 7.32(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s,1H) The starting material was prepared as follows: A mixture of2-(methylamino)ethanol (5.4 g, 72 mmol), 2-bromoethyl methyl ether (10g, 72 mmol) and triethylamine (10 ml, 72 mmol) in acetonitrile (70 ml)was refluxed overnight. After cooling, the solid was filtered and thefiltrate was evaporated. The residue was triturated with ether. Theether layer was separated and evaporated to give2-(N-(2-methoxyethyl)-N-methylamino)ethanol (3 g, 31%). MS-EI: 134 [MH]+¹H NMR Spectrum: (CDCl₃) 2.35(s, 3H); 2.6(t, 2H); 2.65(t, 2H); 3.35(s,3H); 3.5(t, 2H); 3.6(t, 2H) d7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 4-(3-hydroxypropyl)morpholine (102 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.1(m, 2H), 2.4(s, 3H), 2.45(t, 2H),2.45–2.6(s, 4H), 3.6(t, 4H), 4.0(s, 3H), 4.25(t, 2H), 6.15(s, 1H),6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.38(s, 1H), 7.6(s, 1H), 8.5(s, 1H)The starting material was prepared as follows: Morpholine (94 g, 1.08mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54mol) in toluene (750 ml) and the reaction then heated at 80° C. for 4hours. The mixture was allowed to cool to ambient temperature and theprecipitated solid was removed by filtration. The volatiles were removedfrom the filtrate and the resulting yellow oil was purified bydistillation at 0.4–0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40g, 50%) as a colourless oil. b.p. 68–70° C. (~0.5 mmHg) ¹H NMR Spectrum:(DMSOd₆) 1.65–1.78(m, 2H); 2.50(t, 4H); 2.60(t, 2H); 3.68(t, 4H);3.78(t, 2H); 4.90(br d, 1H) e7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 2-(2-methoxyethoxy)ethanol (84 mg) to give6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.42(s, 3H), 3.27(s, 3H), 3.5(t, 2H), 3.65(t,2H), 3.85(t, 2H), 4.0(s, 3H), 4.32(t, 2H), 6.15(s, 1H), 6.9(d, 1H),7.3(s, 1H), 7.35(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) f7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 3-(N,N-dimethylamino)propanol (72 mg) to give7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.0(m, 2H), 2.17(s, 6H), 2.4(s, 3H),3.98(s, 3H), 4.22(t, 2H), 6.14(s, 1H), 6.88(dd, 1H), 7.25(s, 1H), 7.3(d,1H), 7.35(s, 1H), 7.6(s, 1H), 8.47(s, 1H) g7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 3-(1,1-dioxothiomorpholino)-1-propanol (135 mg), (prepared asdescribed for the starting material in Example 5), to give7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.0(m, 2H), 2.38(s, 3H), 2.65(t, 2H),2.9(br s, 4H), 3.1(br s, 4H), 3.96(s, 3H), 4.25(t, 2H), 6.12(s, 1H),6.85(dd, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.37(s, 1H), 7.56(s, 1H), 8.46(s,1H) h 7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline wasreacted with 2-(1H-1,2,4-triazol-1-yl)ethanol (79 mg), (Ann. Phar. Fr.1977, 35, 503–508), to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.42(s, 3H), 3.96(s, 3H), 4.62(m, 2H), 4.75(m,2H), 6.15(s, 1H), 6.9(dd, 1H), 7.27(s, 1H), 7.32(d, 1H), 7.47(s, 1H),7.63(s, 1H), 8.03(s, 1H), 8.51(s, 1H), 8.60(s, 1H) i7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethanol (132 mg), (Arzneim.Forsch. 1966, 16, 1557–1560), to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.2–2.6(m, 10H), 2.4(s, 3H),3.65(t, 2H), 3.85(t, 2H), 4.03(s, 3H), 4.35(m, 2H), 6.16(s, 1H), 6.9(dd,1H), 7.3(s, 1H), 7.35(d, 1H), 7.4(s, 1H), 7.61(s, 1H), 8.5(s, 1H) j7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was reactedwith 2-(2-morpholinoethoxy)ethanol (123 mg) to give6-methoxy-4-(2-methylindol-5-yloxy)-7(2-(2-morpholinoethoxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.40(s, 3H), 2.4–2.5(m, 4H), 2.4–2.6(m, 2H),3.55(t, 4H), 3.6(t, 2H), 3.85(t, 2H), 3.97(br s, 3H), 4.15(br s, 2H),6.15(s, 1H), 6.9(d, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s,1H), 8.48(s, 1H) The starting material was prepared as follows:2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a mixture ofmorpholine (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40 mmol) inacetonitrile (50 ml). The mixture was heated at reflux for 6 hours andthen stirred for 18 hours at ambient temperature. The insolubles wereremoved by filtration and the volatiles were removed from the filtrateby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol (95/5 followed by 90/10 andthen 80/20) to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).MS-(EI): 175 [M.]⁺ ¹H NMR Spectrum: (CDCl₃) 2.5(br s, 4H); 2.59(t, 2H);3.6–3.85(m, 10H)

EXAMPLE 67

A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100mg, 0.29 mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (preparedas described for the starting material in Example 48), and potassiumcarbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85° C. for 3hours, followed by heating at 95° C. for 2 hours. After cooling,ice/water (15 ml) was added and the precipitate was collected byfiltration and dried under vacuum. The solid was purified by columnchromatography eluting with methylene chloride/methanol (95/5) followedby methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give6-methoxy-4-(2-methylindol-5yloxy)-7-(3-piperidinopropoxy)quinazoline(71 mg, 54%).

MS-ESI: 447 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.35–1.4 (m, 2H), 1.45–1.55 (m, 4H), 1.92–2.0(m, 2H), 2.3–2.4 (m, 4H), 2.40 (s, 3H), 2.4–2.5 (m, 2H), 3.97 (s, 3H),4.22 (t, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.27 (s, 1H), 7.8 (d, 1H), 7.35(s, 1H), 7.58 (s, 1H), 8.48 (s, 1H)

The starting material was prepared as follows:

Diethyl azodicarboxylate (3.9 ml, 24.5 mmol) was added in portions to asuspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(5 g, 16.3 mmol), (prepared as described for the starting material inExample 12), 3-bromo-1-propanol (2.21 ml, 24.5 mmol) andtriphenylphosphine (6.42 g, 24.5 mmol) in methylene chloride (50 ml).After stirring for 2 hours at ambient temperature, the volatiles wereremoved under vacuum and the residue was purified by columnchromatography eluting with methylene chloride followed by methylenechloride/methanol (95/5) to give7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(6 g, 86%).

MS-ESI: 427–429 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.12 (s, 9H), 2.32 (t, 2H), 3.7 (t, 2H), 3.9(s, 3H), 4.25 (t, 2H), 5.9 (s, 2H), 7.20 (s, 1H), 7.51 (s, 1H), 8.36 (s,1H)

Elemental analysis: Found C 50.1 H 5.4 N 6.4 C₁₈H₂₃BrN₂O₅ 0.2H₂ORequires C 50.2 H 5.5 N 6.5%

A solution of7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(2.89 g, 6.78 mmol) in piperidine (100 ml) was heated at 100° C. for 1hour. After cooling, the volatiles were removed under vacuum. Theresidue was dissolved in methylene chloride, and washed with saturatedammonium chloride and brine. The organic layer was dried (MgSO₄) and thevolatiles were removed by evaporation. The residue was dried undervacuum to give6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(2.4 g, 83%).

MS-ESI: 432 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.15 (s, 9H), 1.35–1.5 (m, 1H), 1.6–1.8 (m,3H), 1.8–1.9 (d, 2H), 2.2–2.3 (m, 2H), 2.95 (t, 2H), 3.25 (t, 2H), 3.55(d, 2H), 3.95 (s, 3H), 4.25 (t, 2H), 5.94 (s, 2H), 7.24 (s, 1H), 7.56(s, 1H), 8.46 (s, 1H)

A solution of6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(2.35 g, 5.45 mmol) in 7M ammonia in methanol (50 ml) was stirredovernight at ambient temperature. The volatiles were removed undervacuum and the residue was triturated with ether, filtered and washedwith ether followed by ether/methylene chloride (1/1) and dried undervacuum to give6-methoxy-7-(3-piperidinopropoxy)-3,4dihydroquinazolin-4-one (1.65 g,95%).

MS-ESI: 318 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3–1.4 (m, 2H), 1.4–1.55 (m, 4H), 1.85–1.95(m, 2H), 2.35 (br s, 4H), 2.4 (t, 2H), 3.9 (s, 3H), 4.15 (t, 2H), 7.11(s, 1H), 7.44 (s, 1H), 7.9 (s, 1H)

Elemental analysis: Found C 63.5 H 7.4 N 13.1 C₁₇H₂₃N₃O₃ 0.2H₂O RequiresC 63.6 H 7.4 N 13.0%

A solution of6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.5 g,4.7 mmol) in thionyl chloride (15 ml) containing DMF (1.5 ml) was heatedat reflux for 3 hours. After cooling, the volatiles were removed undervacuum. The residue was azeotroped with toluene. The solid waspartitioned between methylene chloride and sodium hydrogen carbonate.The aqueous layer was adjusted to pH10 with 6M aqueous sodium hydroxide.The organic layer was separated, washed with brine, dried (MgSO₄) andthe volatiles were removed by evaporation. The residue was purified bycolumn chromatography to give4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.21 g, 76%).

MS-ESI: 336 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H), 1.5–1.6 (m, 4H), 1.9–2.05(m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H), 4.0 (s, 3H), 4.29 (t, 2H), 7.41(s, 1H), 7.46 (s, 1H), 8.9 (s, 1H)

EXAMPLE 68

Using an analogous procedure to that described in Example 67,4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (10 mg), (preparedas described for the starting material in Example 67), was reacted with5-hydroxyindole (48 mg, 0.36 mmol) to give4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (57 mg,45%).

MS-ESI: 433 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.4 (br s, 2H), 1.45–1.6 (br s, 4H), 1.9–2.1(m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.47(s, 1H), 7.0 (d, 1H), 7.35 (s, 1H), 7.45 (s, 2H), 7.47 (d, 1H), 7.61 (s,1H), 8.49 (s, 1H)

EXAMPLE 69

A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(161 mg, 0.5 mmol), (prepared as described in Example 49),4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine(222 mg, 0.6 mmol), (prepared as described for the starting material inExample 10), and potassium carbonate (188 mg, 1 mol) in DMF (1.6 ml) washeated at 100° C. for 2 hours. After cooling, water was added. Theprecipitate was collected by filtration, washed with water, and driedunder vacuum over phosphorus pentoxide at 60° C. The solid wastriturated with petroleum ether, collected by filtration, washed with amixture of ether/petroleum ether (1/1) and dried under vacuum to give6-methoxy-4(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline(200 mg, 77%).

MS-ESI: 541 [MNa]⁺

¹H NMR Spectrum: (DMSOd₆) 1.1–1.3 (m, 2H), 1.4 (s, 9H), 1.8 (d, 2H),1.95–2.1 (m, 1H), 2.4 (s, 1H), 2.7–2.85 (br s, 2H), 3.95 (s, 3H), 4.05(d, 2H), 6.12 (s, 1H), 6.8% (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.35 (s,1H), 7.55 (s, 1H), 8.45 (s, 1H)

EXAMPLE 70

A solution of6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline(155 mg, 0.3 mmol), (prepared as described in Example 69), in methylenechloride (5 ml) containing TFA (1 ml) was stirred at ambient temperaturefor 30 minutes. The volatiles were removed under vacuum and the residuewas treated with water and adjusted to pH12 with 2M sodium hydroxide.The mixture was extracted with methylene chloride. The organic layer wasdried (MgSO₄), and the volatiles were removed by evaporation. Theresidue was purified by column chromatography eluting with methylenechloride/ethyl acetate/methanol (5/4/1) followed by methylenechloride/methanol (9/1) and by 3M ammonia in methanol/methanol/methylenechloride (5/15/80). After removal of the solvent by evaporation, theresidue was dissolved in the minimum of methylene chloride, ether wasadded followed by petroleum ether. The precipitate was collected byfiltration, washed with ether and dried under vacuum to give6-methoxy-4-(2-methylindol-5yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(120 mg, 96%).

MS-ESI: 419 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.5–1.7 (m, 2H), 2.05 (br d, 2H),2.3–2.4 (m, 1H), 2.4 (s, 3H), 3.05 (t, 2H), 3.4 (d, 2H), 4.09 (s, 3H),4.25 (d, 2H), 6.95 (dd, 1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.6 (s, 1H),7.85 (s, 1H), 9.15 (s, 1H)

EXAMPLE 71

Methoxyacetaldehyde (368 mg, 3.47 mmol) (freshly distilled) followed bysodium triacetoxyborohydride (552 mg, 2.6 mol) were added to a solutionof6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(726 mg, 1.74 mmol), (prepared as described in Example 70), in a mixtureof methylene chloride (15 ml) and methanol (15 ml). After stirring for1.5 hours at ambient temperature, saturated sodium hydrogen carbonatewas added. The volatiles were removed under vacuum and the residue waspartitioned between methylene chloride and water. The organic layer, wasseparated, washed with water, brine, dried (MgSO₄) and the volatileswere removed by evaporation. The residue was purified by columnchromatography eluting with methylene chloride/methanol (80/20). Afterremoval of the solvent, the residue was triturated with ether, collectedby filtration, washed with ether and dried under vacuum at 60° C. togive6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline(392 mg, 47%).

MS-ESI 477 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.6–1.8 (m, 2H), 2.05 (br d, 2H),2.15–2.3 (m, 1H), 2.4 (s, 3H), 3.05 (t, 2H), 3.3 (br s, 2H), 3.32 (s,3H), 3.58 (d, 2H), 3.65 (br s, 2H), 4.05 (s, 3H), 4.18 (d, 2H), 6.2 (s,0.5H (partly exchanged)), 6.92 (dd, 1H), 7.32 (s, 1H), 7.35 (d, 1H),7.55 (s, 1H), 7.8 (s, 1H), 9.15 (s, 1H)

Elemental analysis: Found C 68.0 H 6.8 N 11.8 C₂₇H₃₂N₄O₄ Requires C 68.1H 6.8 N 11.8%

The starting material was prepared as follows:

A solution of 1,1,2-trimethoxyethane (90 g, 750 mmol) in water (570 ml)containing 12 N hydrochloric acid (3.75 ml) was stirred at 40° C. for1.5 hours. After cooling, solid sodium chloride was added and themixture was extracted with ether. The organic layer was dried (MgSO₄).The organic layer was distilled and the fraction from 70–90° C. wascollected to give methoxyacetaldehyde (20.3 g) which was used directlyin the next step.

EXAMPLE 72

Diphenylphosphoryl azide (83 mg, 0.3 mmol) was added in portions to asolution of7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75mg, 0.2 mmol), triethylamine (40 mg, 0.4 mmol) and1-(2-aminoethyl)pyrrolidine (46 mg, 0.4 mmol) in DMF (1.5 ml). Afterstirring for 5 hours at ambient temperature, the mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water, brine, dried (MgSO₄) and the volatiles were removed byevaporation. The residue was purified by column chromatography elutingwith methylene chloride/methanol (9/1) followed by methylene chloride/3Mammonia in methanol (9/1). After removal of the solvent, the solid wastriturated with ether, collected by filtration, washed with ether anddried under vacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline(25 mg, 26%).

MS-ESI: 472 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.8–1.95 (m, 2H), 1.95–2.1 (m, 2H),2.48 (s, 3H), 3.0–3.2 (m, 2H), 3.35 (t, 2H), 3.6 (t, 2H), 3.65 (br s,2H), 4.11 (s, 3H), 6.18 (s, 0.5H, partially exchanged), 6.95 (dd, 1H),7.05 (d, 1H), 7.35 (s, 1H), 7.37 (d, 1H), 7.8 (s, 1H), 7.86 (d, 1H), 8.2(s, 1H), 8.76 (s, 1H)

The starting material was prepared as follows:

Trifluoromethanesulphonic anhydride (338 mg, 1.2 mmol) was added to asuspension of4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, Immol), (prepared as described for the starting material in Example 5),in methylene chloride (2 ml) containing pyridine (2 ml) cooled at 5° C.When the addition was complete, the mixture was left to warm to ambienttemperature and stirred for 1 hour. After removal of the volatiles byevaporation, the residue was partitioned between ethyl acetate/ether andwater. The organic layer was separated, washed with 0.5M hydrochloricacid, followed by water, brine, dried (MgSO₄) and evaporated to give4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline(400 mg, 88%).

MS-ESI: 453–455 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 4.15 (s, 3H), 7.5 (d, 1H), 7.62 (t, 1H), 7.78(d, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 8.77 (s, 1H)

Triethylamine (33 mg, 0.33 mmol) and tert-butyl acrylate (77 mg, 0.6mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008 mmol) andpalladium(II) acetate (1.7 mg, 0.0075 mmol) were added to a solution of4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline(136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the addition wascomplete the reaction flask was purged with argon. The mixture wasstirred at 80–85° C. for 6 hours. After cooling, the mixture waspartitioned between ethyl acetate and water. The aqueous layer wasadjusted to pH6 with 2M hydrochloric acid. The organic layer wasseparated, washed with water, brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography eluting with methylenechloride followed by methylene chloride/ether (95/5). After removal ofthe solvent under vacuum, the solid was triturated with pentane/ether,collected by filtration and dried under vacuum to give4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline(63 mg, 49%).

MS-ESI: 431 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.51 (s, 9H), 4.07 (s, 3H), 6.87 (d, 1H), 7.45(d, 1H), 7.6 (t, 1H), 7.7 (s, 1H), 7.75 (d, 1H), 7.91 (d, 1H), 8.39 (s,1H), 8.65 (s, 1H)

Elemental analysis: Found C 61.1 H 4.8 N 6.6 C₂₂H₂₀ClFN₂O₃ Requires C61.3 H 4.7 N 6.5%

A solution of4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)quinazoline(581 mg, 1.31 mmol) in a mixture of methylene chloride/TFA (2.5 ml/2.5ml) was stirred at ambient temperature for 1.5 hours. After removal ofthe volatiles under vacuum, the residue was partitioned between ethylacetate and water. The aqueous layer was adjusted to pH3 with 0.5Msodium hydroxide. The organic layer was separated and the aqueous layerwas further extracted with ethyl acetate. The combined organic layerswere washed with brine, dried (MgSO₄) and evaporated to give7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline(430 mg, 85%).

¹H NMR Spectrum: (DMSOd₆) 4.08 (s, 3H), 6.9 (d, 1H), 7.45 (s, 1H), 7.6(t, 1H), 7.70 (s, 1H), 7.73 (d, 1H), 7.95 (d, 1H), 8.39 (s, 1H), 8.66(s, 1H)

1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a suspension of7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline(105 mg, 0.28 mmol) and 5-hydroxy-2methylindole (82 mg, 0.56 mmol),(prepared as described for the starting material in Example 48), in DMSO(1.5 ml). After stirring for 2 hours at ambient temperature, the mixturewas partitioned between ethyl acetate and water. The aqueous layer wasadjusted to pH3 with 2M hydrochloric acid. The organic layer was washedwith water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography eluting with methylenechloride/methanol (95/5 followed by 90/10 and 70/30) to give7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75mg, 71%).

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 4.06 (s, 3H), 6.15 (s, 1H), 6.82(d, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.68 (s, 1H), 7.84 (d,1H), 8.25 (s, 1H), 8.55 (s, 1H)

EXAMPLE 73

A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(321 mg, 1 mmol), (prepared as described in Example 49),1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperatureovernight. After addition of water, the precipitate was collected byfiltration, washed with water and dried over phosphorus pentoxide at 60°C. to give7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280mg, 70%).

MS-ESI: 398 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.2–2.35 (m, 2H), 2.4 (s, 3H), 3.85 (t, 2H),4.0 (s, 3H), 4.32 (t, 2H), 6.15 (s, 1H), 6.88 (d, 1H), 7.27 (s, 1H), 7.3(d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)

EXAMPLE 74

A solution of7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (150mg, 0.38 mmol), (prepared as described in Example 73), in1-methylpiperazine (2 ml) was heated at 100° C. for 2 hours. Aftercooling, the mixture was partitioned between ethyl acetate and aqueous5% sodium hydrogen carbonate. The organic layer was separated, washedwith water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography on an isolute column eluting withmethanol/ethyl acetate/methylene chloride (1/4/5 followed by 1/9/0) and3M ammonia in methanol/methanol/methylene chloride (5/10/80). Afterremoval of the solvent under vacuum, the solid was dissolved in theminimum of methylene chloride and ether/petroleum ether was added. Theprecipitate was collected by filtration, and dried under vacuum to give6-methoxy-4(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline(55 mg, 32%).

MS-ESI: 462 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD, 60° C.) 2.2–2.3 (m, 2H), 2.4 (s, 3H),2.9 (s, 3H), 3.4–3.5 (m, 4H), 3.5–3.8 (m, 6H), 4.07 (s, 3H), 4.4 (t,2H), 6.95 (d, 1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H),8.95 (s, 1H)

EXAMPLE 75

Triphenylphosphine (262 mg, 1 mmol) and N,N-diethylethanolamine (88 mg,0.75 mmol) were added to a suspension of7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (160 mg, 0.5mmol), (prepared as described in Example 49), in methylene chloride (5ml), followed by the addition, in portions, of diethyl azodicarboxylate(165 μl, 1 mmol). After stirring for 1 hour at ambient temperature, thevolatiles were removed under vacuum. The residue was purified by columnchromatography eluting with methylene chloride/methanol (95/5) followedby methylene chloride/3M ammonia in methanol (90/10) to give7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(147 mg, 70%).

MS-ESI 421 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.0 (t, 6H), 2.41 (s, 3H), 2.6 (q, 4H), 2.88(t, 2H), 3.97 (s, 3H), 4.24 (t, 2H), 6.14 (s, 1H), 6.89 (dd, 1H), 7.25(s, 1H), 7.32 (d, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.48 (s, 1H)

Elemental analysis: Found C 66.2 H 6.9 N 13.1 C₂₄H₂₈N₄O₃ 0.8H₂O RequiresC 66.3 H 6.9 N 12.9%

EXAMPLE 76

Using an analogous procedure to that described in Example 75,7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1mmol), (prepared as described in Example 49), was reacted with2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (294 mg, 1.2 mmol) togive6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((]-tertbutoxycarbonyl)piperidin-4-yloxy)ethoxy)quinazoline(420 mg, 76%).

MS-ESI: 549 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 1.3–1.5 (m, 2H), 1.7–1.9 (m, 2H),2.38 (s, 3H), 3.0 (br t, 2H), 3.5–3.7 (m, 3H), 3.85 (m, 2H), 3.98 (s,3H), 4.3 (t, 2H), 6.12 (s, 1H), 6.85 (d, 1H), 7.22 (s, 1H), 7.3 (d, 1H),7.4 (s, 1H), 7.55 (s, 1H), 8.48 (s, 1H)

The starting material was prepared as follows:

tert-Butoxycarbonyl anhydride (1.52 g, 7 mmol) in acetone (3.5 ml) wasadded to a solution of 4,4-(ethylenedioxy)piperidine (1 g, 7 mmol) inacetone/trichloromethane (3.5 ml/3.5 ml) cooled at 0° C. After stirringfor 4 hours at ambient temperature, the volatiles were removed undervacuum. The residue was dissolved in ether and the ether solution waswashed with water, brine, dried (MgSO₄) and evaporated to give4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (1.7 g, quant.).

¹H NMR Spectrum: (CDCl₃): 1.46 (s, 9H), 1.65 (t, 4H), 3.5 (t, 4H), 3.97(s, 4H)

Freshly distilled boron trifluoride etherate (52 μl, 0.41 mmol),followed by sodium cyanoborohydride (38 mg, 0.6 mmol) were added to asolution of 4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (100 mg,0.41 mmol) in THF (1.4 ml) cooled at 0° C. After stirring for 6 hours atambient temperature, boron trifluoride etherate (52 μl) and sodiumcyanoborohydride (26 mg, 0.41 mmol) were added. After stirring overnightat ambient temperature, the mixture was partitioned between ethylacetate and 2M sodium hydroxide. The organic layer was washed withwater, brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography eluting with methylene chloride/methanol (95/5)followed by methylene chloride/methanol/3M ammonia in methanol (80/15/5)to give 2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (42 mg, 42%).

MS-ESI: 268 [MNa]⁺

¹H NMR Spectrum: (CDCl₃) 1.48 (s, 9H), 1.5–1.6 (m, 2H), 1.8–1.9 (m, 2H),2.0 (t, 1H), 3.053.15 (m, 2H), 3.5 (m, 1H), 3.57 (t, 2H), 3.7–3.9 (m,4H)

EXAMPLE 77

A solution of6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethoxy)quinazoline(379 mg, 0.69 mmol), (prepared as described in Example 76), in methylenechloride (7 ml) containing TFA (2.5 ml) was stirred for 1.5 hours atambient temperature. After removal of the volatiles under vacuum, theresidue was partitioned between ethyl acetate and water. Solid sodiumhydrogen carbonate and 2N sodium hydroxide were added to adjust theaqueous layer to about pH10. The organic layer was washed with water,followed by brine, dried (MgSO₄) and evaporated. The residue wastriturated with ether, filtered, washed with ether and dried undervacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline(164 mg, 53%).

¹HNMR Spectrum: (DMSOd₆) 1.2–1.4 (m, 2H), 1.8–1.9 (m, 2H), 2.47 (s, 3H),2.4–2.5 (m, 2H), 2.9–3.0 (d, 2H), 3.3–3.5 (m, 1H), 3.95 (s, 2H), 4.0 (s,3H), 4.35 (s, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.28 (s, 1H), 7.32 (d,1H), 7.41 (s, 1H), 7.60 (s, 1H), 8.49 (s, 1H)

MS-ESI: 448 μM.]⁺

EXAMPLE 78

A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(193 mg, 0.6 mmol), (prepared as described in Example 49),4-(2-hydroxyethoxy)pyridine (166 mg, 1.2 mmol), (J. Chem. Soc. PerkinII, 1987, 1867), in methylene chloride (5 ml) containingtriphenylphosphine (330 mg, 1.26 mmol) and diisopropyl azodicarboxylate(255 mg, 1.26 mmol) was stirred at ambient temperature for 2 hours. Theprecipitate was filtered, triturated with ether followed by ethylacetate, and dried under vacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline(142 mg, 54%).

¹HNMR Spectrum: (DMSOd₆) 2.40 (s, 3H), 3.97 (s, 3H), 4.52 (t, 2H), 4.58(t, 2H), 6.14 (s, 1H), 6.89 (dd, 1H), 7.07 (d, 2H), 7.26 (s, 1H), 7.31(d, 1I), 7.46 (s, 1H), 7.61 (s, 1H), 8.41 (d, 2H), 8.5 (s, 1H)

MS-ESI: 443 [MH]⁺

Elemental analysis Found C 66.6 H 5.0 N 12.5 C₂₅H₂₂N₄O₄ 0.12 CH₂Cl₂Requires C 66.9 H 5.0 N 12.4%

EXAMPLE 79

A suspension of6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline(148 mg, 0.31 mmol), (prepared as described in Example 149), inmethylene chloride (4 ml) containing TFA (1 ml) was stirred for 1 hour.After removing the volatiles under vacuum, the residue was azeotropedwith toluene. The residue was dissolved in methylene chloride (3 ml) andtriethylamine (215 μl, 1.5 mmol) was added followed by methanesulphonylchloride (48 μl, 0.62 mmol). After stirring for 1 hour at ambienttemperature, the mixture was partitioned between methylene chloride andwater. The organic layer was separated, washed with water, brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with ethylacetate/methanol (99/1 followed by97/3). After evaporation of the solvent, the solid was triturated withether, filtered, washed with ether and dried under vacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline(54 mg, 38%).

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 2.93 (s, 3H), 3.0 (s, 3H), 3.62(t, 2H), 4.0 (s, 3H), 4.38 (t, 2H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.26(s, 1H), 7.3 (d, 1H), 7.43 (s, 1H), 7.61 (s, 1H), 8.49 (s, 1H)

MS-ESI: 457 [MH]⁺

EXAMPLE 80

A solution of6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinazoline(76 mg, 0.17 mmol), (prepared as described in Example 77), inacrylonitrile (0.5 ml), methylene chloride (1 ml) and methanol (1 ml)was stirred overnight at ambient temperature. After removal of thevolatiles under vacuum the residue was purified by column chromatographyeluting with methylene chloride/methanol (98/2 followed by 95/5 and90/10). The residue was triturated with ethyl acetate and ether. Theresulting solid was filtered and dried under vacuum to give7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(73 mg, 86%).

¹H NMR Spectrum: (DMSOd₆) 1.4–1.55 (m, 2H), 1.8–1.9 (m, 2H), 2.15 (t,2H), 2.4 (s, 3H), 2.55 (t, 2H), 2.65 (t, 2H), 2.7–2.8 (m, 2H), 3.4–3.5(m, 1H), 3.85 (m, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 1H), 6.9 (dd,1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)

MS-ESI: 502 [MH]⁺

Elemental analysis Found C 67.0 H 6.2 N 14.0 C₂₈H₃₁N₅O₄ Requires C 67.1H 6.2 N 14.0%

EXAMPLE 81

A solution of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(100 m g, 0.31 mmol), (prepared as described for the starting materialin Example 9), 6-hydroxyindole (50 mg, 0.37 mmol) and potassiumcarbonate (64 mg, 0.466 mmol) in DMF (1 ml) was heated at 95° C. for 4hours. After cooling, the mixture was diluted with methylene chlorideand poured onto a silica column. The product was eluted with methylenechloride, followed by methylene chloride/methanol (80/20 followed by70/30 and 50/50). After removal of the solvent by evaporation, theprecipitate was triturated with ether, filtered and dried under vacuumto give6-methoxy-4-(indol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(90 mg, 69%).

¹H NMR Spectrum: (DMSOd₆) 1.85 (br s, 4H), 2.15–2.25 (m, 2H), 2.85–3.15(m, 6H), 4.01 (s, 3H), 4.32 (t, 2H), 6.5 (s, 1H), 6.95 (dd, 1H), 7.32(s, 1H), 7.4 (s, 2H), 7.6 (d, 1H), 7.65 (s, 1H), 8.52 (s, 1H)

MS-ESI: 419 [MH]⁺

EXAMPLE 82

Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added to a solutionof 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.34 mmol),triphenyl phosphine (189 mg, 0.72 mol), and 3-pyrrolidinopropan-1-ol (89mg, 0.686 mmol), (J. Org. Chem. 1988, 53, 3164), in methylene chloride(2.5 ml). After stirring overnight at ambient temperature, the solid wasfiltered. The filtrate was purified by column chromatography elutingwith ethyl acetate/methylene chloride (1/1) followed by ethylacetate/methylene chloride/methanol (4/5/1), methylene chloride/methanol(9/1) and 3N ammonia in methanol/methylene chloride (1/9). After removalof the solvent, the residue was triturated with ether, filtered, anddried under vacuum to give4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline (49mg, 35%)

¹H NMR Spectrum: (DMSOd₆) 1.8–2.0 (m, 2H), 2.0–2.15 (m, 2H), 2.2–2.32(m, 2H), 2.41 (s, 3H), 3.0–3.2 (m, 2H), 3.4 (t, 2H), 3.6–3.7 (m, 2H),4.35 (t, 2H), 6.2 (s, 1H), 6.95 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.5(s, 1H), 7.57 (dd, 1H), 8.5 (d, 1H), 9.15 (s, 1H)

MS-ESI: 403 [MH]⁺

The starting material was prepared as follows:

Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol)and the mixture was heated at 148° C. for 30 minutes.7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc.section B 1967, 449), was added and the mixture maintained at 148° C.for 24 hours. The reaction mixture was allowed to cool, the solution waspoured on to water (170 ml) and the aqueous mixture adjusted to pH3 withconcentrated hydrochloric acid. The precipitate was collected byfiltration, washed with water, ether and dried under vacuum to give7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.

m.p. 267–269° C.

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 5.32(s, 2H); 7.25(d, 1H);7.32–7.52(m, 6H); 8.12(d, 1H); 8.99(s, 1H)

MS-ESI: 252 [MH]⁺

Elemental analysis: Found C 71.4 H 4.9 N 10.7 C₁₅H₁₂N₂O₂ 0.04H₂ORequires C 71.2 H 4.8 N 11.1%

A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (1 g, 43.6 mmol)and DMF (1 ml) in thionyl chloride (100 ml) was heated at reflux for 1.5hours. Excess thionyl chloride was removed by evaporation and theresidue azeotroped with toluene. The residue was partitioned betweenmethylene chloride and water and saturated aqueous sodium hydrogencarbonate was added until the aqueous layer was at about pH9. Theorganic layer was separated, washed with water, brine, dried (MgSO₄) andevaporated to give 7-benzyloxy-4-chloroquinazoline (10.5 g, 89%).

¹H NMR Spectrum: (DMSOd₆) 5.4 (s, 2H); 7.35–7.65 (m, 6H); 8.2 (d, 1H);9.0 (s, 1H)

MS-ESI: 270 [MH]⁺

A solution of 7-benzyloxy-4-chloroquinazoline (2 g, 7.4 mmol),5-hydroxy-2-methylindole (1.3 g, 8.9 mmol), (prepared as described forthe starting material in Example 48), in DMF (20 ml) containingpotassium carbonate (1.53 g, 11.1 mmol) was stirred at 80° C. for 3hours. After cooling, the mixture was poured in portions into ice/water.The precipitate was filtered and washed with water and dried undervacuum. The solid was dissolved in methylene chloride and was purifiedby column chromatography eluting with ethyl acetate and methylenechloride (1/1) to give 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline(2.28 g, 81%).

MS-ESI: 382 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.41 (s, 3H), 5.4 (s, 2H), 6.15 (s, 1H), 6.9(dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.4 (d, 1H), 7.4–7.5 (m, 4H), 7.55(d, 2H), 8.32 (d, 1H), 8.6 (s, 1H).

10% Palladium on charcoal (200 mg) followed by ammonium formate (4.34 g,69 mmol) were added to a solution of7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (1.75 g, 4.58 mmol) inDMF (60 ml). After stirring for 1 hour at ambient temperature, themixture was filtered. The filtrate was evaporated. The residue wastriturated with water, filtered, washed with ethyl acetate, and driedunder vacuum to give 7-hydroxy-4-(2-methylindol-5yloxy)quinazoline (1.24g, 93%).

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.17(s, 1H), 7.25–7.3 (m, 2H), 7.30 (d, 1H), 8.24 (d, 1H), 8.5 (s, 1H)

EXAMPLES 83–89

Using an analogous procedure to that described in Example 82, theappropriate alcohols were reacted with7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared as describedfor the starting material in Example 82), to give the compoundsdescribed in Table VI below.

TABLE VI

Example Weight Yield MS-ESI number (mg) % [MH]⁺ R Note 83 34 24 412

a 84 45 32 405

b 85  5  3 417

c 86 56 35 467

d 87 63 44 419

e 88 24 17 403

f 89 84 63 387

g a 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reactedwith 3-(methylsulphonyl)-1-propanol (95 mg), (prepared as described forthe starting material in Example 50), to give7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆, CF₃COOD) 2.2–2.3(m, 2H), 2.4(s, 3H), 3.05(s, 3H),3.3–3.45(m, 2H), 4.4(t, 2H), 6.2(s, 1H), 6.95(dd, 1H), 7.38(s, 1H),7.4(d, 1H), 7.5(s, 1H), 7.6(dd, 1H), 8.5(d, 1H), 9.2(s, 1H) Elementalanalysis Found C 60.2 H 5.3 N 10.6 C₂₁H₂₁N₃O₄S 0.4 DMF Requires C 60.5 H5.4 N 10.8% b 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg)was reacted with 4-(2-hydroxyethyl)morpholine (90 mg) to give4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆, CF₃COOD) 2.4(s, 3H), 3.1–3.3(m, 2H), 3.62(d, 2H),3.7–3.9(m, 4H), 4.05(d, 2H), 4.7(t, 2H), 6.2(s, 0.5H, partiallyexchanged), 6.95(dd, 1H), 7.35(s, 1H), 7.39(d, 1H), 7.6(s, 1H), 7.65(dd,1H), 8.55(d, 1H), 9.15(s, 1H) Elemental analysis Found C 67.2 H 6.0 N13.5 C₂₃H₂₄N₄O₃ 0.3 H₂O Requires C 67.4 H 6.1 N 13.7% c7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with1-(3-hydroxypropyl)piperidine (98 mg) to give4-(2-methylindol-5-yloxy)-7-(3-(piperidin-1-yl)propoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆, CF₃COOD) 1.2–1.5(m, 2H), 1.6–1.8(m, 2H),1.8–1.9(m, 2H), 2.25–2.35(m, 2H), 2.45(s, 3H), 2.95(t, 2H), 3.25–3.3(m,2H), 3.55(d, 2H), 4.4(t, 2H), 6.95(dd, 1H), 7.4(s, 1H), 7.45(d, 1H),7.5(s, 1H), 7.6(d, 1H), 8.55(d, 1H), 9.15(s, 1H) d7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with3-(1,1-dioxothiomorpholino)-1-propanol (133 mg), (prepared as describedfor the starting material in Example 5), to give4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.0(m, 2H), 2.4(s, 3H), 1.6–1.7(m, 2H),2.9(br s, 4H), 3.1(br s, 4H), 4.25(t, 2H), 6.12(s, 1H), 6.85(d, 1H),7.22(s, 1H), 7.3(d, 1H), 7.3–7.4(m, 2H), 8.25(d, 1H), 8.55(s, 1H) e7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with4-(3-hydroxypropyl)morpholine (100 mg), (prepared as described for thestarting material in Example 60), to give4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 1.95–2.05(m, 2H), 2.42(s, 3H), 2.5(t, 2H), 2.55(t,4H), 3.6(t, 4H), 4.3(t, 2H), 6.18(s, 1H), 6.9(dd, 1H), 7.3(s, 1H),7.35(d, 1H), 7.3–7.4(m, 2H), 8.3(d, 1H), 8.6(s, 1H) Elemental analysisFound C 66.5 H 6.2 N 12.7 C₂₄H₂₆N₄O₃ 0.14 CH₂Cl₂ 0.7 H₂O Requires C 66.7H 6.4 N 13.0% f 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg)was reacted with 1-(2-hydroxyethyl)piperidine (89 mg) to give4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆) 1.4–1.5(br s, 2H), 1.5–1.7(br s, 4H), 2.42(s,3H), 2.5–2.7(br s, 4H), 2.8–3.0(br s, 2H), 4.35(br s, 2H), 6.18(s, 1H),6.9(dd, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.4(d, 1H), 7.42(s, 1H), 8.3(d,1H), 8.6(s, 1H) Elemental analysis Found C 69.0 H 6.6 N 13.4 C₂₄H₂₆N₄O₂0.8 H₂O Requires C 69.1 H 6.7 N 13.4% g7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted with2-(1H-1,2,4-triazol-1-yl)ethanol (78 mg), (Ann. Phar. Fr. 1977, 35,503–508), to give4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.4(s, 3H), 4.6(m, 2H), 4.7(m, 2H), 6.15(s,1H), 6.9(dd, 1H), 7.28(s, 1H), 7.3(d, 2H), 7.4(s, 1H), 8.02(s, 1H),8.3(d, 1H), 8.6(s, 1H), 8.65(s, 1H) Elemental analysis Found C 63.7 H4.8 N 21.5 C₂₁H₁₈N₆O₂ 0.5 H₂O Requires C 63.8 H 4.8 N 21.3%

EXAMPLE 90

A solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (423 mg,1.45 mmol), (prepared as described for the starting material in Example82), triphenylphosphine (685 mg, 2.61 mmol),4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (500 mg, 2.32 mmol),(prepared as described for the starting material in Example 10), anddiisopropyl azodicarboxylate (528 mg, 2.61 mmol) in methylene chloride(18 ml) was stirred overnight at ambient temperature. The mixture wasthen poured onto a column of silica and eluted with ethyl acetate. Afterevaporation of the solvent, the residue was triturated with ether,filtered, and dried under vacuum to give7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline(478 mg, 68%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.4 (m, 2H), 1.42 (s, 9H), 1.85 (d, 2H),2.0–2.1 (m, 1H), 2.42 (s, 3H), 2.7–2.9 (br s, 2H), 3.95–4.05 (m, 2H),4.1 (d, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.33 (d, 1H), 7.38(s, 1H), 7.35–7.4 (m, 1H), 8.3 (d, 1H), 8.6 (s, 1H)

MS-ESI: 489 [MH]⁺

Elemental analysis Found C 68.7 H 6.7 N 11.3 C₂₈H₃₂N₄O₄ Requires C 68.8H 6.6 N 11.5%

EXAMPLE 91

To a suspension of4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg,0.32 mmol) in methylene chloride (2.5 ml) was added triphenylphosphine(179 mg, 0.628 mmol), 1-(2-hydroxyethyl)pyrrolidine (75 mg, 0.65 mmol)followed by diisopropyl azodicarboxylate (134 μl, 0.68 mmol) inportions. After stirring overnight at ambient temperature the mixturewas poured onto a column of silica and eluted with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol(4/5/1) followed by methylene chloride/methanol (9/1). After removal ofthe solvent, the solid was triturated with ether, filtered, washed withether and dried under vacuum to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline(51 mg, 37%).

¹H NMR Spectrum: (DMSOd₆) 1.6–1.75 (m, 4H), 2.12 (s, 3H), 2.28 (s, 3H),2.52 (br s, 4H), 3.85 (t, 2H), 3.93 (s, 3H), 4.25 (t, 2H), 6.8 (d, 1H),7.17 (s, 1H), 7.22 (d, 1H), 7.33 (s, 1H), 7.54 (s, 1H), 8.43 (s, 1H)

The starting material was prepared as follows:

To a solution of 2,3-dimethyl-5-methoxyindole (175 mg, 1 mmol), (J.Chem. Soc. 1957, 3175–3180) in methylene (5 ml) cooled at −60° C. wasadded boron tribromide (210 μl, 2.2 mmol) dropwise. After completion ofaddition, the mixture was left to warm up to ambient temperature and wasstirred for 1 hour. Water was added and the pH was adjusted to 6 with 2Nsodium hydroxide. The mixture was extracted with ethyl acetate and theorganic layer was separated, washed with brine, dried (MgSO₄) andevaporated to give 2,3-dimethyl-5-hydroxyindole (124 mg, 77%).

¹H NMR Spectrum: (DMSOd₆) 2.1 (s, 3H); 2.3 (s, 3H); 6.5 (dd, 1H); 6.65(d, 1H); 7.0 (d, 1H); 8.45 (s, 1H)

Under nitrogen, to a solution of 2,3-dimethyl-5-hydroxyindole (643 mg, 4mmol), in DMF (10 ml) was added potassium carbonate (690 mg, 5 mmol).After stirring for 15 minutes at ambient temperature,7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared asdescribed for the starting material in Example 1), was added. Themixture was heated at 90° C. for 2 hours followed by 30 minutes at 95°C. After cooling, the mixture was poured onto water (100 ml) cooled at5° C. The precipitate was filtered, washed with water, followed by etherand dried under vacuum to give7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (1.4 g,95%).

¹H NMR Spectrum: (DMSOd₆) 2.15 (s, 3H); 2.35 (s, 3H); 4.02 (s, 3H) 5.4(s, 2H); 6.9 (dd, 1H); 7.22 (d, 1H); 7.3 (d, 1H); 7.35–7.6 (m, 6H); 7.65(s, 1H); 8.5 (s, 1H)

A solution of7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (2 g, 4.7mmol) in DMF (120 ml) containing ammonium formate (11 gr, 174 mmol) and10% palladium on charcoal (200 mg) was stirred for 2.5 hours at ambienttemperature. The mixture was filtered, and the filtrate was evaporatedunder vacuum. The residue was triturated with ether and the solid wasfiltered, washed with water followed by ether and dried under vacuum at50° C. to give4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1.1 g,69%).

¹H NMR Spectrum: (DMSOd₆) 2.1 (s, 3H); 2.32 (s, 3H); 3.97 (s, 3H); 7.85(dd, 1H); 7.2 (bs, 2H); 7.25 (d, 1H); 7.58 (s, 1H); 8.4 (s, 1H)

EXAMPLES 92–106

Using an analogous procedure to that described in Example 91, theappropriate alcohol was reacted with4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline, (preparedas described for the starting material in Example 91), to give thecompounds described in the Table VII below.

TABLE VII

Example Weight MS-ESI HPLC* number (mg) Yield % [MH]⁺ R RT (mm) Note 9291 65 431

— a 93 78 55 438

— b 94 34 27 435

— c 95 39 33 407

— d 96 58 44 449

— e 97 58 47 421

— f 98 85 66 447

— g 99 24 18 447

— h 100 110 82 461

— i 101 9 7 447

— j 102 81 62 463

3.4 k 103 75 57 451

— l 104 96 65 511

— m 105 103 78 457

— n 106 64 49 456

— o *HPLC conditions 2) as described hereinbefore. a4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg)was reacted with 2-(1H-1,2,4-triazol-1-yl)ethanol (74 mg), (Ann. Phar.Fr. 1977, 35, 503–508), to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.10(s, 3H), 2.30(s, 3H), 3.93(s, 3H), 4.52(m,2H), 4.55–4.65(m, 2H), 6.85(d, 1H), 7.2(s, 1H), 7.25(d, 1H), 7.4(d, 1H),7.58(s, 1H), 8.0(s, 1H), 8.48(s, 1H), 8.58(s, 1H) b4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg)was reacted with 2-(2-methoxyethoxy)ethanol (78 mg) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.14(s, 3H), 2.35(s, 3H), 3.3(s, 3H), 3.5(t,2H), 3.65(t, 2H), 3.85(t, 2H), 4.0(s, 3H), 4.32(t, 2H), 6.9(d, 1H),7.25(d, 1H), 7.28(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) c4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with N,N-diethylethanolamine (68 mg) to give7-(2-(N,N-diethylamino)ethoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 1.05(t, 6H), 2.15(s, 3H), 2.35(s, 3H),2.6–2.7(m, 4H), 2.92(br s, 2H), 4.0(s, 3H), 4.25(t, 2H), 6.9(dd, 1H),7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) d4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with N,N-dimethylethanolamine (52 mg) to give7-(2-(N,N-dimethylamino)ethoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 9H), 2.85(br s, 2H),4.0(s, 3H), 4.35(t, 2H), 6.87(dd, 1H), 7.22(s, 1H), 7.3(d, 1H), 7.42(s,1H), 7.6(s, 1H), 8.5(s, 1H) e4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 4-(2-hydroxyethyl)morpholine (59 mg) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-morpholinoethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 3H), 3.25–3.4(m, 2H),3.65(d, 2H), 3.7–3.8(m, 4H), 4.0–4.1(m, 2H), 4.1(s, 3H), 4.7(t, 2H),6.95(dd, 1H), 7.3(s, 1H), 7.35(d, 1H), 7.6(s, 1H), 7.8(s, 1H), 9.0(s,1H) f 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97mg) was reacted with 3-(N,N-dimethylamino)propan-1-ol (60 mg) to give7-(3-(N,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 1.95–2.05(m, 2H), 2.15(s, 3H), 2.2(s, 6H),2.35(s, 3H), 2.45(t, 2H), 4.0(s, 3H), 4.25(t, 2H), 6.9(dd, 1H), 7.22(d,1H), 7.3(d, 1H), 7.37(s, 1H), 7.6(s, 1H), 8.5(s, 1H) g4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 1-(2-hydroxyethyl)-2-pyrrolidinone (75 mg) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.05(m, 4H), 2.15(s, 3H), 2.25(t, 2H),2.35(s, 3H), 3.65(t, 2H), 4.0(s, 3H), 4.35(t, 2H), 6.9(d, 1H), 7.25(s,1H), 7.3(d, 1H), 7.45(s, 1H), 7.62(s, 1H), 8.5(s, 1H) h4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 2-(2-hydroxyethyl)piperidine (75 mg) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.0–1.15(m, 1H), 1.25–1.4(m, 2H), 1.5(br s,1H), 1.65(d, 1H), 1.7–1.8(m, 1H), 1.8–1.9(m, 2H), 2.15(s, 3H), 2.35(s,3H), 2.5(d, 1H), 2.6–2.7(m, 1H), 2.9–3.0(m, 1H), 4.0(s, 3H), 4.2–4.35(m,2H), 6.88(dd, 1H), 7.2(s, 1H), 7.27(d, 1H), 7.4(s, 1H), 7.6(s, 1H),8.5(s, 1H) i4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 1-(2-hydroxyethyl)pyrrolidin-2,5-dione (83 mg) to give4-(2,3-dimethylindol-5-yloxy)-7-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.12(s, 3H), 2.35(s, 3H), 2.68(s, 4H), 3.85(t,2H), 3.95(s, 3H), 4.35(t, 2H), 6.88(dd, 1H), 7.22(s, 1H), 7.25(d, 1H),7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) j4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 1-methyl-3-piperidinemethanol (75 mg) to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline.k 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg)was reacted with 4-(3-hydroxypropyl)morpholine (75 mg), (prepared asdescribed for the starting material in Example 60), to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.95–2.05(m, 2H), 2.15(s, 3H), 2.35(s, 3H),2.42(br s, 4H), 2.5(t, 2H), 3.6(m, 4H), 4.0(s, 3H), 4.25(t, 2H),6.85(dd, 1H), 7.25(d, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s,1H). l 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97mg) was reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (77mg), (prepared as described for the starting material in Example 59), togive4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 6H), 2.65(t, 2H), 2.9(t,2H), 3.25(s, 3H), 3.45(t, 2H), 4.0(s, 3H), 4.3(t, 2H), 6.9(dd, 1H),7.22(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.6(s, 1H), 8.5(s, 1H) m4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 3-(1,1-dioxothiomorpholino)-1-propanol (112 mg), (preparedas described for the starting material in Example 5), to give4-(2,3-dimethylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 1.95–2.05(m, 2H), 2.15(s, 3H), 2.35(s, 3H),2.7(t, 2H), 2.95(br s, 4H), 3.15(br s, 4H), 4.0(s, 3H), 4.29(t, 2H),6.9(dd, 1H), 7.25(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.61(s, 1H), 8.5(s,1H) n 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97mg) was reacted with 2-(4-pyridyloxy)ethanol (81 mg), (J. Chem. Soc.Perkin Trans 2, 1987, 12, 1867), to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 3H), 4.0(s, 3H), 4.55(m,2H), 4.6(m, 2H), 6.88(dd, 1H), 7.08(d, 2H), 7.22(s, 1H), 7.28(d, 1H),7.48(s, 1H), 7.6(s, 1H), 8.42(d, 2H), 8.5(s, 1H), 10.78(s, 1H) o4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97 mg) wasreacted with 3-(methylsulphonyl)-1-propanol (80 mg), (prepared asdescribed for the starting material in Example 50), to give4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.8–1.9(m, 2H), 2.15(s, 3H), 2.25–2.35(m, 2H),2.35(s, 3H), 3.0(s, 3H), 4.02(s, 3H), 4.35(t, 2H), 6.9(dd, 1H), 7.25(s,1H), 7.3(d, 1H), 7.4(s, 1H), 7.7(s, 1H), 8.52(s, 1H)

EXAMPLE 107

Using an analogous procedure to that described in Example 91,7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 2-(2-methoxyethoxy)ethanol (70 mg) to give4-(indol-5yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (50mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 3.3 (s, 3H), 3.5 (m, 2H), 3.65 (m, 2H), 3.85(m, 2H), 4.02 (s, 3H), 4.35 (t, 2H), 6.58 (s, 1H), 7.0 (dd, 1H), 7.4 (s,1H), 7.45 (br s, 2H), 7.47 (d, 1H), 7.61 (s, 1H), 8.5 (s, 1H)

MS-ESI: 410 [MH]+

The starting material was prepared as follows:

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (3 g, 10 mmol),(prepared as described for the starting material in Example 1),5-hydroxyindole (1.46 g, 11 mmol) in DMF (30 ml) containing potassiumcarbonate (2.75 g, 20 mmol) was heated at 95° C. for 2 hours. Aftercooling the mixture was poured onto water (100 ml). The precipitate wasfiltered, washed with water and dried under vacuum at 50° C. overphosphorus pentoxide. The solid was triturated with ether, filtered,washed with ether and dried under vacuum to give7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.5 g, 88%).

¹H NMR Spectrum: (DMSOd₆) 4.02 (s, 3H), 5.4 (s, 2H), 6.5 (s, 1H), 7.0(dd, 1H), 7.4–7.6 (m, 9H), 7.65 (s, 1H), 8.5 (s, 1H), 11.23 (s, 1H)

MS-ESI: 398 [MH]+

A solution of 7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (8 g,20 mmol) in DMF (50 ml) and methylene chloride (100 ml) containing 10%palladium on charcoal (2 g) was hydrogenated at 1.8 atmospheres pressureuntil uptake of hydrogen had ceased. The solution was filtered, thecatalyst was washed with DMF and the filtrate was evaporated. Theresidue was purified by column chromatography eluting with methylenechloride, followed by methylene chloride/methanol (95/5 and 90/10).After evaporation of the solvent, the residue was triturated with ether,filtered and dried under vacuum to give7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (2.7 g; 44%).

¹H NMR Spectrum: (DMSOd₆) 4.0 (s, 3H), 6.46 (s, 1H), 7.01 (dd, 1H), 7.2(s, 1H), 7.4–7.5 (m, 3H), 7.6 (s, 1H), 8.41 (s, 1H)

EXAMPLES 108–118

Using an analogous procedure to that described in Example 107, theappropriate alcohol was reacted with7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline, (prepared as describedfor the starting material in Example 107), to give the compoundsdescribed in the Table VIII below.

TABLE VIII

Example Weight MS-ESI number (mg) Yield % [MH]⁺ R Note 108 58 49 407

r 109 14 13 379

s 110 55 48 393

t 111 27 23 405

u 112 58 47 421

v 113 63 52 419

w 114 64 53 419

x 115 106 84 435

y 116 76 62 423

z 117 113 81 483

aa 118 24 19 429

bb r 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) wasreacted with N,N-diethylethanolamine (68 mg) to give7-(2-(N,N-diethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline. s7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg was reacted withN,N-dimethylethanolamine (52 mg) to give7-(2-(N,N-dimethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.3(s, 6H), 2.8(t, 2H), 4.0(s, 3H), 4.3(t,2H), 6.45(s, 1H), 7.0(dd, 1H), 7.4–7.5(m, 4H), 7.6(s, 1H), 8.5(s, 1H) t7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 3-(N,N-dimethylamino)propan-1-ol (60 mg) to give7-(3-(N,N-dimethylamino)propoxy)-4-(iodol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.05(m, 2H), 2.21(s, 6H), 2.45(t, 2H),4.02(s, 3H), 4.25(t, 2H), 6.47(s, 1H), 7.0(dd, 1H), 7.38(s, 1H),7.35–7.4(m, 2H), 7.45(d, 1H), 7.6(s, 1H), 8.5(s, 1H) u7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith (2S)-2-(hydroxymethyl)-1-methylpyrrolidine (67 mg) to give(2S)-4-(indol-5-yloxy)-6-methoxy-7-(1-methylpyrrolidin-2-yl)quinazoline.v 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 3-(N,N-diethylamino)-1-propanol (76 mg) to give7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 0.95(t, 6H), 1.9–2.0(m, 2H), 2.5(m, 4H),2.6(t, 2H), 4.0(s, 3H), 4.25(t, 2H), 6.48(s, 1H), 7.0(dd, 1H), 7.38(s,1H), 7.42–7.5(m, 3H), 7.6(s, 1H), 8.5(s, 1H) w7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 2-(2-hydroxyethyl)piperidine (75 mg) to give4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆) 1.45–1.75(m, 3H), 1.75–1.85(m, 2H), 2.0–2.1(m,1H), 2.1–2.2(m, 1H), 2.25–2.35(m, 1H), 2.95(t, 1H), 3.3–3.4(m, 2H),4.1(s, 3H), 4.4–4.5(m, 2H), 6.5(s, 1H), 7.05(dd, 1H), 7.45–7.6(m, 4H),7.75(s, 1H), 9.0(s, 1H) x7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 1-(2-hydroxyethyl)piperidine (75 mg) to give4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆) 1.1–1.3(m, 1H), 1.35–1.5(m, 1H), 1.65–1.8(m, 2H),1.8–1.9(m, 2H), 3.1(t, 2H), 3.6(d, 2H), 3.65(t, 2H), 4.1(s, 3H), 4.7(t,2H), 6.5(d, 1H), 7.05(dd, 1H), 7.45(s, 1H), 7.5–7.55(m, 2H), 7.61(s,1H), 7.8(s, 1H), 9.0(m, 1H) y7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 4-(3-hydroxypropyl)morpholine (84 mg), (prepared as described forthe starting material in Example 60), to give4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 1.9–2.1(m, 2H), 2.4(br s, 4H), 2.5(t, 2H), 3.6(t,4H), 4.0(s, 3H), 4.25(t, 2H), 6.45(s, 1H), 7.0(dd, 1H), 7.4(s, 1H),7.4–7.45(m, 2H), 7.47(d, 1H), 7.6(s, 1H), 8.5(s, 1H) z7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (77 mg), (prepared asdescribed for the starting material in Example 59), to give4-(indol-5-yloxy)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.35(s, 3H), 2.65(t, 2H), 2.9(t, 2H), 3.25(s,3H), 3.45(t, 2H), 4.0(s, 3H), 4.3(t, 2H), 6.45(s, 1H), 7.05(dd, 1H),7.4–7.5(m, 4H), 7.6(s, 1H), 8.5(s, 1H) aa7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 3-(1,1-dioxothiomorpholino)-1-propanol (112 mg), (prepared asdescribed for the starting material in Example 5), to give7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.0(m, 2H), 2.65(m, 2H), 2.9(br s, 4H),3.15(br s, 4H), 4.0(s, 3H), 4.25(t, 2H), 6.5(s, 1H), 7.0(dd, 1H),7.35–7.5(m, 4H), 7.65(s, 1H), 8.5(s, 1H) bb7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was reactedwith 2-(4-pyridyloxy)ethanol (81 mg), (J. Chem. Soc. Perkin Trans 2,1987, 12, 1867), to give4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline.

EXAMPLE 119

A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200mg, 0.59 mmol), (prepared as described for the starting material inExample 67), 6-hydroxyindole (96 mg, 0.715 mmol) in DMF (3 ml)containing cesium carbonate (291 mg, 0.894 mmol) was heated at 90° C.for 4 hours. After cooling, the mixture was diluted with water, theprecipitate was filtered, washed with water and dried under vacuum. Thesolid was purified by column chromatography eluting with methylenechloride/methanol (90/10 increasing to 50/50) to give4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (240 mg,93%).

¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H), 1.45–1.55 (m, 4H), 1.9–2.05(m, 2H), 2.3–2.4 (m, 4H), 2.45 (t, 2H), 4.0 (s, 3H), 4.22 (t, 2H), 6.5(s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35–7.40 (m, 2H), 7.55–7.65 (m,2H), 8.5 (s, 1H)

MS-ESI: 433 [MH]⁺

Elemental analysis Found C 68.4 H 6.4 N 12.8 C₂₅H₂₈N₄O₃ 0.4 H₂O RequiresC 68.3 H 6.6 N 12.7%

EXAMPLE 120

A solution of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline(200 mg, 0.6 mmol), (prepared as described for the starting material inExample 50), and 6hydroxyindole (97 mg, 0.73 mmol) in DMF (3 ml)containing potassium carbonate (125 mg, 0.91 mmol) was heated at 90° C.for 2.5 hours. After cooling, water was added. The precipitate wasfiltered, washed with water and dried under vacuum. The residue wastriturated with ether, filtered, washed with ether and dried undervacuum to give4-(indol-6-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (130mg, 50%).

¹H NMR Spectrum: (DMSOd₆) 2.2–2.35 (m, 2H), 3.05 (s, 3H), 3.3 (m, 2H),4.0 (s, 3H), 4.35 (t, 2H), 6.48 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.4(2s, 2H), 7.6 (d, 1H), 7.65 (s, 1H), 7.9 (s, 1H)

MS-ESI: 428 [MH]⁺

Elemental analysis Found C 56.2 H 4.9 N 9.3 C₂₁H₂₁N₃O₅S 1.1 H₂O RequiresC 56.4 H 5.2 N 9.4%

EXAMPLE 121

Using an analogous procedure to that described for Example 120,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59mmol), (prepared as described for the starting material in Example 1),was reacted with 6-hydroxyindole (95 mg, 0.71 mmol) to give4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (155 mg,60%).

¹H NMR Spectrum: (DMSOd₆) 1.95–2.05 (m, 2H), 2.4 (br s, 4H), 2.48 (t,2H), 3.6 (t, 4H), 4.0 (s, 3H), 4.27 (t, 2H), 6.5 (s, 1H), 6.93 (dd, 1H),7.3 (s, 1H), 7.4 (br s, 2H), 7.6 (d, 1H), 7.61 (s, 1H), 8.5 (s, 1H)

MS-ESI: 435 [MH]⁺

Elemental analysis Found C 62.0 H 6.2 N 12.1 C₂₄H₂₆N₄O₄ 1.6 H₂O RequiresC 62.2 H 6.4 N 12.1%

EXAMPLE 122

A suspension of7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline(150 mg, 0.31 mmol), (prepared as described in Example 90), in methylenechloride (2 ml) and TFA (1.5 ml) was stirred for 1 hour at ambienttemperature. After removal of the volatiles under vacuum the residue wasazeotroped with toluene. The residue was partitioned between methylenechloride and water and the aqueous layer was adjusted to pH11. Theorganic layer was separated, washed with brine, dried (MgSO₄), andevaporated. The residue was triturated with ether, filtered, washed withether and dried under vacuum to give4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (80 mg,67%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.5–1.65 (m, 2H), 2.0 (d, 2H),2.15–2.3 (m, 1H), 2.4 (s, 3H), 2.95 (t, 2H), 3.38 (d, 2H), 4.2 (d, 2H),6.2 (s, 0.5H, partially exchanged), 6.9 (dd, 1H), 7.35 (s, 1H), 7.4 (d,1H), 7.5 (s, 1H), 7.58 (dd, 1H), 8.5 (d, 1H), 9.1 (s, 1H)

MS-ESI: 389 [MH]⁺

Elemental analysis Found C 68.9 H 6.2 N 13.7 C₂₃H₂₄N₄O₂ 0.2 H₂O 0.12Requires C 69.0 H 6.2 N 13.9% CH₂Cl₂

EXAMPLE 123

Using an analogous procedure to that described for Example 71,4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (150 mg,0.386 mmol), (prepared as described in Example 122), was reacted withmethoxyacetaldehyde (83 mg, 0.772 mmol), (prepared as described for thestarting material in Example 71), to give7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4(2-methylindol-5-yloxy)quinazoline(80 mg, 46%).

¹H NMR Spectrum: (DMSOd₆) 1.3–1.42 (m, 2H), 1.7–1.9 (m, 3H), 2.0 (t,2H), 2.4 (s, 3H), 2.48 (t, 2H), 2.92 (d, 2H), 3.22 (s, 3H), 3.42 (t,2H), 4.05 (d, 2H), 6.15 (s, 1H), 6.88 (dd, 1H), 7.25 (s, 1H), 7.3 (d,1H), 7.35 (s, 1H), 7.37 (d, 1H), 8.28 (d, 1H), 8.6 (s, 1H)

MS-ESI: 447 [MH]⁺

Elemental analysis Found C 68.4 H 6.7 N 12.2 C₂₆H₃₀N₄O₃ 0.5 H₂O RequiresC 68.6 H 6.9 N 12.3%

EXAMPLE 124

Diethyl azodicarboxylate (117 mg, 0.67 mmol) was added in portions to asolution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(120 mg, 0.37 mmol), (prepared as described in Example 49), and3-(ethylsulphonyl)-1-propanol (74 mg, 0.48 mmol) in methylene chloride(3.5 ml) and triphenylphosphine (176 mg, 0.67 mmol). After stirring for2 hours at ambient temperature, the residue was poured onto a column ofsilica and eluted with ethyl acetate/methylene chloride (1/1) followedby methylene chloride/methanol (97/3 followed by 95/5). After removal ofthe solvent under vacuum, the residue was triturated with ether,filtered and dried under vacuum to give7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(93 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 1.25 (t, 3H), 2.2–2.3 (m, 2H), 2.4 (s, 3H),3.2 (q, 2H), 3.3 (t, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.15 (s, 1H), 6.9(dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.4 (s, 1H), 7.62 (s, 1H), 8.5 (s,1H)

MS-ESI: 456 [MH]⁺

Elemental analysis Found C 60.3 H 5.6 N 9.2 C₂₃H₂₅N₃O₅S Requires C 60.6H 5.5 N 9.2%

The starting material was prepared as follows:

A solution of ethylthiopropanol (1.2 g, 10 mmol) in methylene chloride(30 ml) containing 3-chloroperoxybenzoic acid (5 g, 20 mmol) was stirredat ambient temperature for 30 minutes. The precipitate was filtered,washed with methylene chloride and the filtrate was poured onto a columnof aluminium oxide and eluted with methylene chloride, followed bymethylene chloride/methanol (95/5 and 90/10). After removal of thesolvent, the residue was dissolved in methylene chloride, dried (MgSO₄)and evaporated to give 3-(ethylsulphonyl)-1-propanol (1.05 g, 69%).

¹H NMR Spectrum: (DMSOd₆) 1.25 (t, 3H), 1.75–1.9 (m, 2H), 3.0–3.2 (m,4H), 3.5 (q, 2H), 4.7 (t, 1H)

MS-ESI: 153 [MH]⁺

EXAMPLE 125

Using an analogous procedure to that described for Example 124,4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (120 mg,0.36 mol), (prepared as described for the starting material in Example91), was reacted with 3-(ethylsulphonyl)-1-propanol (71 mg, 0.46 mol),(prepared as described for the starting material in Example 124), togive4-(2,3-dimethylindol-5-yloxy)-7-(3-ethylsulphonylpropoxy)-6-methoxyquinazoline(96 mg, 57%).

¹H NMR Spectrum: (DMSOd₆) 1.25 (t, 3H), 2.15 (s, 3H), 2.2–2.3 (m, 2H),2.35 (s, 3H), 3.2 (q, 2H), 3.3 (t, 2H), 4.02 (s, 3H), 4.35 (t, 2H), 6.9(dd, 1H), 7.22 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.63 (s, 1H), 8.51 (s,1H)

MS-ESI: 470 [MH]⁺

Elemental analysis Found C 60.6 H 6.0 N 8.8 C₂₄H₂₇N₃O₅S 0.4 H₂O RequiresC 60.5 H 5.9 N 8.8%

EXAMPLE 126

Using an analogous procedure to that described for Example 124,7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (128 mg, 0.4mmol), (prepared as described in Example 49), was reacted with4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine (119 mg, 0.52 mmol)overnight to give7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5yloxy)quinazoline(34 mg, 16%).

¹H NMR Spectrum: (DMSOd₆) 1.05–1.2 (m, 2H), 1.42 (s, 9H), 1.62–1.85 (m,5H), 2.42 (s, 3H), 2.62–2.82 (m, 2H), 3.94.0 (m, 2H), 4.0 (s, 3H), 4.25(t, 2H), 6.17 (s, 1H), 6.9 (dd, 1H), 7.3 (d, 1H), 7.32 (d, 1H), 7.4 (s,1H), 7.6 (s, 1H), 8.5 (s, 1H)

MS-ESI: 533 [MH]⁺

Elemental analysis Found C 67.8 H 6.9 N 10.5 C₃₀H₃₆N₄O₅ Requires C 67.7H 6.8 N 10.5%

The starting material was prepared as follows:

A solution of 4-(2-hydroxyethyl)pyridine (1.8 g, 14.6 mol) in aceticacid (15 ml) containing platinum oxide (200 mg) was hydrogenated for 20hours at 3.3–4 atmospheres pressure. After filtration, the filtrate wasevaporated and azeotroped twice with toluene. The residue was trituratedwith 2N sodium hydroxide and solid sodium hydroxide was added to adjustthe pH to 13. The volatiles were removed under vacuum and the residuewas triturated with ether, filtered, washed with methylene chloride, anddried under vacuum to give 2-(piperidin-4-yl)-1-ethanol (860 mg, 46%).

¹H NMR Spectrum: (DMSOd₆,CF₃COOD) 1.3–1.5 (m, 4H), 1.6–1.7 (m, 1H),1.7–1.9 (d, 2H), 1.75 (t, 2H), 3.25 (d, 2H), 3.55 (t, 2H)

A solution of 2-(piperidin-4-yl)-1-ethanol (830 mg, 6.4 mmol) in DMF (5ml) containing tertbutyl dicarbonate anhydride (1.4 g, 6.4 mmol) wasstirred at ambient temperature for 48 hours. After removal of thevolatiles under vacuum, the residue was partitioned between ether andwater. The organic layer was separated, washed with water, brine, dried(MgSO₄) and evaporated to give4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine (1 g, 68%).

¹H NMR Spectrum: (DMSOd₆) 0.9–1.1 (m, 2H), 1.3–1.6 (m, 3H), 1.4 (s, 9H),1.6 (d, 2H), 2.5–2.8 (br s, 2H), 3.45 (dd, 2H), 3.9 (d, 2H), 4.35 (t,1H)

EXAMPLE 127

Using an analogous procedure to that described for Example 121,4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.47mol), (prepared as described for the starting material in Example 1),was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57 mol), (Eur. J.Med. Chem. 1975, 10, 187), to give6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline(157 mg, 73%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.25–2.35 (m, 2H), 2.38 (s, 3H), 3.15(t, 2H), 3.35 (t, 2H), 3.5 (d, 2H), 3.68 (t, 2H), 4.0 (d, 2H), 4.05 (s,3H), 4.35 (t, 2H), 6.18 (s, 1H), 6.9 (d, 1H), 7.22 (s, 1H), 7.45 (d,1H), 7.52 (s, 1H), 7.8 (s, 1H), 9.05 (s, 1H)

MS-ESI: 449 [MH]⁺

Elemental analysis Found C 66.4 H 6.4 N 12.4 C₂₅H₂₈N₄O₄ 0.2 H₂O RequiresC 66.4 H 6.3 N 12.4%

EXAMPLE 128

Using an analogous procedure to that described for the synthesis of4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,(prepared as described in Example 122),7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(400 mg, 0.75 mmol), (prepared as described in Example 126), was used togive 6-methoxy(2-methylindol-5yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoline (284 mg,87%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.3–1.5 (m, 2H), 1.8–2.0 (m, 5H), 2.4(s, 3H), 2.9 (t, 2H), 3.3 (d, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.2 (s,1H), 6.95 (dd, 1H), 7.35 (s, 1H), 7.37 (d, 1H), 7.52 (s, 1H), 7.8 (s,1H), 9.1 (s, 1H)

MS-ESI: 433 [MH]⁺

EXAMPLE 129

Diethyl azodicarboxylate (65 μl, 0.4 mmol) was added in portions to asuspension of4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol), triphenylphosphine (107 mg, 0.4 mmol),(E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (40 mg, 0.28 mmol) in DMF (0.4 ml)and dichloromethane (1.5 ml) cooled at 0° C. The reaction mixture wasleft to warm up to ambient temperature and was stirred overnight. Themixture was poured onto a column of silica and was eluted with methylenechloride followed by methylene chloride/methanol (98/2), followed bymethylene chloride/3N ammonia in methanol (95/5 and 90/10) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline(51 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 1.6–1.7 (m, 4H), 2.15 (s, 3H), 2.3 (s, 3H),2.4 (br s, 4H), 3.1 (d, 2H), 3.97 (s, 3H), 4.7 (d, 2H), 5.8–6.0 (m, 2H),7.15 (s, 1H), 7.22 (d, 1H), 7.3 (d, 1H), 7.55 (s, 1H), 7.87 (s, 1H), 8.3(s, 1H), 9.4 (s, 1H), 10.62 (s, 1H)

MS-ESI: 458 [MH]⁺

The starting material was prepared as follows:

Thionyl chloride (9.3 ml, 128 mmol) was added in portions to a stirredsolution of 2-butyne-1,4-diol (10 g, 116 mmol) in toluene (15 ml) andpyridine (10.3 ml) cooled at 0° C. The mixture was stirred for 3.5 hoursat ambient temperature and then poured onto ice water. The mixture wasextracted with ether, the organic layer was washed with saturatedaqueous sodium hydrogen carbonate solution and then brine, dried (MgSO₄)and the volatiles removed by evaporation. The residue was purified bycolumn chromatography eluting with petroleum ether/ether (7/3) to give4-chlorobut-2-yn-1-ol (4.74 g, 39%).

¹H NMR Spectrum: (CDCl₃) 1.68(t, 1H); 4.18(d, 2H); 4.33(d, 2H)

Pyrrolidine (7.8 ml, 94 mmol) was added dropwise to a solution of4-chlorobut-2-yn-1-ol (4.74 g, 45 mmol) in toluene (40 ml) and themixture stirred and heated at 60° C. for 1 hour. The volatiles wereremoved by evaporation and the residue was purified by chromatographyeluting with methylene chloride/methanol (96/4) to give4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%).

¹H NMR Spectrum: (CDCl₃) 1.82(t, 4H); 2.63(t, 4H); 3.44(t, 2H), 4.29(t,2H)

A solution of 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 31 mmol) in THF(20 ml) was added dropwise to a suspension of lithium aluminium hydride(2.35 g, 62 mmol) in anhydrous THF (8 ml) and the mixture stirred andheated at 60° C. for 2 hours. The mixture was cooled to 5° C. and 2Maqueous sodium hydroxide solution (28 ml) was added dropwise. Theresulting suspension was filtered and the volatiles removed from thefiltrate by evaporation. The residue was dissolved in a mixture ofmethylene chloride/ethyl acetate, dried (MgSO₄) and the solvent removedby evaporation. The residue was purified by column chromatography onaluminum oxide eluting with methylene chloride/methanol (97/3) to give(E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.09 g, 70%).

¹H NMR Spectrum: (CDCl₃) 1.82(m, 4H); 2.61(m, 4H); 3.17(m, 2H); 4.13(s,2H); 5.84(m, 2H)

A solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (7 g, 23 mmol),(prepared as described for the starting material in Example 1), and5-amino-2,3-dimethylindole (4.5 g, 28 mmol) in isopropanol (90 ml)containing 6.2 N hydrogen chloride in isopropanol (380 μl) was heated atrelux for 3 hours and stirred overnight at ambient temperature. Themixture was triturated with ether and the solid was filtered, washedwith ether and dried under vacuum to give7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline (10.5g, quant.).

¹H NMR Spectrum: (DMSOd₆) 2.16 (s, 3H), 2.33 (s, 3H), 4.0 (s, 3H), 5.34(s, 2H), 7.2 (d, 1H), 7.32 (d, 1H), 7.35–7;55 (m, 7H), 8.2 (s, 1H), 8.7(s, 1H), 10.9 (s, 1H), 11.15 (s, 1H)

MS-ESI: 425 [MH]+

Ammonium formate (20 g, 326 mmol) and 10% palladium on carbon (1 g) wereadded to a solution of7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline (10 g,22 mmol) in DMF (100 ml) and methanol (300 ml). After stirring for 3hours at ambient temperature, aqueous ammonia (120 ml) was added. Theprecipitate was filtered, washed with water and dried under vacuum. Theresidue was triturated with ethyl acetate and ether and was filtered,dried under vacuum and purified by column chromatography eluting withmethanol/methylene chloride (5/95 followed by 10/90) to give4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (5.5 g,75%).

¹H NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 2.35 (s, 3H), 3.97 (s, 3H), 7.0(s, 1H), 7.22 (d, 1H), 7.3 (d, 1H), 7.55 (s, 1H), 7.85 (s, 1H), 8.28 (s,1H), 9.35 (s, 1H), 10.2 (br s, 1H), 10.62

(s, 1H)

MS-ESI: 335 [MH]+

EXAMPLES 130–145

Using an analogous procedure to that described in Example 129,4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol), (prepared as described for the starting material in Example129), was reacted with the appropriate alcohol to give the compoundsdescribed in Table IX.

TABLE IX

Example MS-ESI number Weight (mg) Yield % [MH]⁺ R Note 130 10 11 458

a 131 63 69 450

b 132 5 6 443

c 133 35 36 475

d 134 53 51 510

e 135 56 58 469

f 136 4 4.6 415

g 137 29 35 406

h 138 49 56 432

i 139 8 8.6 481

j 140 15 15 477

k 141 38 42 446

l 142 69 72 470

m 143 21 21 492

n 144 36 40 440

o 145 31 33 460

p a 4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68mg, 0.2 mmol) was reacted with3-(5-methyl-[1,2,4]-triazol-1-yl)propan-1-ol (40 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(5-methyl-1H-[1,2,4]-triazol-1-yl)propoxy)quinazoline.The starting material was prepared as follows: Under argon,1,2,4-triazole (13.8 g, 200 mmol) was added to a solution of sodiumethoxide (freshly prepared from sodium (4.6 g) and ethanol (250 ml)).After complete dissolution, 3-bromopropan-1-ol (18 ml, 200 mmol) wasadded dropwise. The mixture was refluxed for 18 hours and the solid wasfiltered and washed with ethanol. The filtrate was evaporated and theresidue was purified by column chromatography eluting with methylenechloride/methanol (9/1) to give 3-(1,2,4-triazol-1-yl)propan-1-ol (22.8g, 90%). ¹H NMR Spectrum: (CDCl₃): 2.12(m, 2H); 2.6(br s, 1H); 3.65(t,2H); 4.35(t, 2H); 7.95(s, 1H); 8.1(s, 1H) To a solution of3-(1,2,4-triazol-1-yl)propan-1-ol (7 g, 55 mmol) in DMF (70 ml) wasadded tertbutyldimethylsilyl chloride (9.1 g, 60 mmol) followed by DMAP(336 mg, 2.7 mmol) followed by imidazole (4.5 gr, 66 mmol). Afterstirring overnight at ambient temperature, the volatiles were removedunder vacuum and the residue was partitioned between water and ethylacetate/ether. The organic layer was separated, washed with water,brine, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride/ether (6/4) to give3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (11.1 gr,84%). MS-EI: 242 [MH]+ ¹H NMR Spectrum: (CDCl₃) 0.25(s, 6H); 0.9(s, 9H);2.05(m, 2H); 3.52(t, 2H); 4.25(t, 2H); 7.9(s, 1H); 8.02(s, 1H) To asolution of 3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane(7 g, 29 mmol) in DMF (100 ml) cooled at −70° C. was added 2.5 Mn-butyllithium (17.4 ml) over 45 minutes. After stirring for 90 minutesat −70° C., methyl iodide (3.6 ml, 58 mmol) was added. After stirringfor 2 hours at ambient temperature, the mixture was poured ontosaturated ammonium chloride. The mixture was then diluted with ether andethyl acetate. The organic layer was separated, washed with aqueoussodium thiosulphate followed by brine, dried (MgSO₄) and evaporated togive3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)propane(7.3 g, 98%). MS-EI: 256 [MH]+ ¹H NMR Spectrum: (CDCl₃) 0.25(s, 6H);0.85(s, 9H); 2.0(, 2H); 2.4(s, 3H); 3.52(t, 2H); 4.15(t, 2H); 7.72(s,1H) To a solution of ammonium fluoride (10.4 g, 280 mmol) in methanol(110 ml) was added a solution of3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)propane(7.2 g, 28 mmol) in methanol (30 ml). The mixture was refluxed for 4.5hours. After cooling, silica (100 g) was added and the volatiles wereremoved under vacuum. The residue was added onto a column of silica andeluted with a mixture of methylene chloride/ethyl acetate (1/1) followedby methylene chloride/methanol (9/1) to give3-(5-methyl-[1,2,4]-triazol-1-yl)propan-1-ol (3.65 g, 92%). MS-ESI: 142[MH]+ ¹H NMR Spectrum: (CDCl₃) 2.05(m, 2H); 2.5(s, 3H); 3.62(t, 2H);4.25(t, 2H); 7.8(s, 1H) b4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol(38 mg), (prepared as described for the starting material in Example59), to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 6H), 2.65(t, 2H), 2.85(t,2H), 3.25(s, 3H), 3.45(t, 2H), 3.95(s, 3H), 4.2(t, 2H), 7.15(s, 1H),7.22(s, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 9.4(s,1H), 10.62(s, 1H) c4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-(1-methylimidazol-2-yl)ethanol (36 mg), (EP06751112 A1), to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.32(s, 3H), 3.2(t, 2H), 3.7(s,3H), 3.95(s, 3H), 4.45(t, 2H), 6.8(s, 1H), 7.05(s, 1H), 7.15(s, 1H),7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.88(s, 1H), 8.32(s, 1H), 9.4(s,1H), 10.62(s, 1H) d4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (45mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.0(m, 2H), 2.15(2s, 6H), 2.0–2.9(m, 8H),2.32(s, 3H), 2.45(t, 2H), 3.95(s, 3H), 4.2(t, 2H), 7.1(s, 1H), 7.22(d,1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 9.4(s, 1H),10.62(s, 1H) The starting material was prepared as follows:3-Bromopropan-1-ol (20 ml, 20 mmol) was added dropwise to a solution of1-methylpiperazine (29 ml, 26 mmol) in ethanol (200 ml). Potasiumcarbonate (83 gr, 60 mmol) was added and the mixture was refluxed for 20hours. After cooling, the solid was filtered and the filtrate wasevaporated. The residue was triturated with ether, filtrate andevaporated. The residue was distilled at about 60–70° C. under about 0.2mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g, 53%). ¹H NMRSpectrum: (CDCl₃) 1.72(m, 2H); 2.3(s, 3H); 2.2–2.8(m, 8H); 2.6(t, 2H);3.8(t, 2H); 5.3(br s, 1H) e4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (55mg), (prepared as described for the starting material in Example 5), togive4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.0(m, 2H), 2.5(s, 9H), 2.65(t, 2H),2.9(br s, 4H), 3.15(br s, 4H), 3.95(s, 3H), 4.25(t, 2H), 7.2(s, 1H),7.85(s, 1H), 8.0(dd, 1H), 8.15(d, 1H), 8.2(s, 1H), 8.45(s, 1H), 9.6(s,1H), 10.95(s, 1H) f4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-(N-methyl-N-(4-pyridyl)amino)ethanol (43mg), (EP 0359389), to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.35(s, 3H), 3.07(s, 3H), 3.85(t,2H), 3.95(s, 3H), 4.3(t, 2H), 6.7(d, 2H), 7.15(s, 1H), 7.22(d, 1H),7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.15(d, 2H), 8.3(s, 1H), 9.4(s,1H), 10.65(s, 1H) g4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-furanmethanol (28 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-furylmethoxy)quinazoline.h 4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-N,N-dimethylethanolamine (25 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N,N-dimethylamino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.25(s, 6H), 2.32(s, 3H), 2.72(t,2H), 3.95(s, 3H), 4.2(t, 2H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H),7.55(s, 1H), 7.85(s, 1H), 8.32(s, 1H), 9.4(s, 1H), 10.6(s, 1H) i4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 1-(2-hydroxyethyl)pyrrolidine (33 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.65–1.75(m, 4H), 2.15(s, 3H), 2.35(s, 3H),2.55–2.65(m, 4H), 2.9(t, 2H), 3.95(s, 3H), 4.25(t, 2H), 7.15(s, 1H),7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.32(s, 1H), 9.4(s,1H), 10.62(s, 1H) j4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with triethylene glycol monomethyl ether (47 mg)to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)quinazoline.k 4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 5,5-dimethyl-1,3-dioxane-2-ethanol (46 mg) togive7-(2-(5,5-dimethyl-1,3-dioxan-2-yl)ethoxy)-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 0.7(s, 3H), 1.15(s, 3H), 2.05–2.1(m, 2H),2.1(s, 3H), 2.6(s, 3H), 3.42(d, 2H), 3.57(d, 2H), 4.0(s, 3H), 4.22(t,2H), 4.7(t, 1H), 7.2(s, 1H), 7.82(s, 1H), 8.0(dd, 1H), 8.17(d, 1H),8.3(s, 1H), 8.45(s, 1H), 9.6(s, 1H), 10.95(s, 1H) l4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 1-(2-hydroxyethyl)piperidine (37 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.3–1.45(m, 2H), 1.45–1.6(m, 4H), 2.15(s, 3H),2.35(s, 3H), 2.45(br s, 4H), 2.75(t, 2H), 3.95(s, 3H), 4.25(t, 2H),7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s,1H), 9.4(s, 1H), 10.62(s, 1H) m4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol(44 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.32(s, 3H), 3.1(s, 3H), 3.9(s,3H), 3.95(t, 2H), 4.35(t, 2H), 6.85(dd, 1H), 7.15(s, 1H), 7.20(d, 1H),7.28(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 8.58(d, 1H), 8.9(d,1H), 9.4(s, 1H), 10.62(s, 1H) The starting material was prepared asfollows: A solution of 4-bromo-3,6-dichloro-pyridazine (1.11 g, 5 mmol),(J. Chem. Soc., Perkin Trans I, 1974, 696), and 2-(methylamino)ethanol(0.75 g, 10 mmol) in isopropanol (10 ml) was heated at reflux for 30minutes. The solvent was removed by evaporation, the residue waspartitioned between methylene chloride and water and the aqueous layerwas adjusted to pH9 with solid potassium carbonate. The organic layerwas separated, washed with brine, dried (MgSO₄) and the solvent removedby evaporation. The residue was triturated with ether, collected byfiltration and dried under vacuum to give2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (1 g, 90%). ¹HNMR Spectrum: (CDCl₃) 2.1(br s, 1H); 3.09(s, 3H); 3.71(t, 2H); 3.93(t,2H); 6.8(s, 1H) MS-ESI: 221[MH]⁺ A mixture of2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (444 mg, 2 mmol)and 10% palladium-on-charcoal catalyst (150 mg) in ethanol (15 ml),methanol (5 ml) and aqueous ammonia (15 ml) was stirred under hydrogenat 3 atmospheres pressure for 4 hours. The catalyst was removed byfiltration and the solvent removed from the filtrate by evaporation. Theresidue was dissolved in methylene chloride, the insoluble material wasremoved by filtration and the solvent was removed from the filtrate byevaporation. The residue was purified by column chromatography onneutral aluminum oxide eluting with methylene chloride/methanol (95/5followed by 90/10). The purified product was triturated with petroleumether, the solid product was collected by filtration and dried undervacuum to give 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg,91%). ¹H NMR Spectrum: (CDCl₃) 3.06(s, 3H); 3.57(t, 2H); 3.89(t, 2H);6.52(dd, 1H); 8.48(d, 1H); 8.54(d, 1H) MS-ESI: 153 [MH]⁺ n4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 2-(2-morpholinoethoxy)ethanol (50 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.18(s, 3H), 2.35(s, 3H), 2.35–2.45(m, 4H),2.45–2.5(m, 2H), 3.5–3.55(m, 4H), 3.65(t, 2H), 3.8–3.85(m, 2H), 3.95(s,1H), 4.25(m, 2H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H),7.85(s, 1H), 8.3(s, 1H), 9.4(s, 1H), 10.62(s, 1H) The starting materialwas prepared as follows: 2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) wasadded to a mixture of morpholine (2.58 g, 30 mmol) and potassiumcarbonate (5.5 g, 40 mmol) in acetonitrile (50 ml). The mixture washeated at reflux for 6 hours and then stirred for 18 hours at ambienttemperature. The insolubles were removed by filtration and the volatileswere removed from the filtrate by evaporation. The residue was purifiedby column chromatography eluting with methylene chloride/methanol (95/5followed by 90/10 and then 80/20) to give 2-(2-morpholinoethoxy)ethanol(600 mg, 34%). ¹H NMR Spectrum: (CDCl₃) 2.5(br s, 4H); 2.59(t, 2H);3.6–3.85(m, 10H) MS-(EI): 175 [M.]⁺ o4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 3-(2-hydroxyethyl)pyridine (35 mg) to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(3-pyridyl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H), 2.32(s, 3H), 3.15(t, 2H), 3.95(s,3H), 4.4(t, 2H), 7.2(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.35(dd, 1H),7.55(s, 1H), 7.8(d, 1H), 7.85(s, 1H), 8.32(s, 1H), 8.45(dd, 1H), 8.6(s,1H), 9.4(s, 1H), 10.68(s, 1H) p4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg,0.2 mmol) was reacted with 1-(3-hydroxypropyl)pyrrolidin-2-one (41 mg)to give4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.9–2.05(m, 4H), 2.12(s, 3H), 2.15–2.3(m, 2H),2.6(s, 3H), 3.3–3.45(m, 4H), 4.0(s, 3H), 4.15(t, 2H), 7.15(s, 1H),7.82(s, 1H), 8.0(dd, 1H), 8.17(d, 1H), 8.3(s, 1H), 8.45(s, 1H), 9.6(s,1H), 10.95(s, 1H)

EXAMPLE 146

Using an analogous procedure to that described for Example 121,4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150 mg, 0.47mmol), (prepared as described for the starting material in Example 9),was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56 mol), (Eur. J.Med. Chem. 1975, 10, 187), to give6-methoxy-4-(2-methylindol-6yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(170 mg, 85%).

¹H NMR Spectrum: (DMSOd₆) 1.65–1.8 (m, 4H), 1.95–2.05 (m, 2H), 2.42 (s,3H), 2.5 (br s, 1H), 2.6 (t, 2H), 4.0 (s, 3H), 4.27 (t, 2H), 6.2 (s,1H), 6.85 (dd, 1H), 7.2 (s, 1H), 7.4 (s, 1H), 7.45 (d, 1H), 7.6 (s, 1H),8.5 (s, 1H)

MS-ESI: 433 [MH]⁺

Elemental analysis Found C 68.3 H 6.4 N 12.8 C₂₅H₂₈N₄O₃ 0.4 H₂O RequiresC 68.3 H 6.6 N 12.7%

EXAMPLE 147

Using an analogous procedure to that described in Example 123,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoline(120 mg, 0.28 mmol) was used to give7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(55 mg, 40%).

¹H NMR Spectrum: (DMSOd₆) 1.15–1.3 (m, 2H), 1.4–1.55 (m, 1H), 1.65–1.8(m, 4H), 1.95 (t, 2H), 2.4 (s, 3H), 2.42 (t, 2H), 2.85 (d, 2H), 3.25 (s,3H), 3.42 (t, 2H), 4.0 (s, 3H), 4.22 (t, 2H), 6.15 (s, 1H), 6.85 (dd,1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.38 (s, 1H), 7.59 (s, 1H), 8.5 (s, 1H).

MS-ESI: 491 [MH]

Elemental analysis Found C 65.3 H 7.1 N 10.9 C₂₈H₃₄N₄O₄ 1.3 H₂O RequiresC 65.4 H 7.2 N 10.9%

EXAMPLE 148

Using an analogous procedure to that described in Example 120 OR 121 PERPP, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.48mmol), (prepared as described for the starting material in Example 1),was reacted with 1,2-dimethyl-5-hydroxyindole (92 mg, 0.57 mol),(Tetrahedron 1994, 50, 13433), to give4-(1,2-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(163 mg, 74%).

¹H NMR Spectrum: (DMSOd₆) 1.95–2.1 (m, 2H), 2.4 (br s, 4H), 2.45 (s,3H), 2.5 (t, 2H), 3.65 (t, 4H), 3.75 (s, 3H), 4.0 (s,3H), 4.25 (t, 2H),6.25 (s, 1H), 6.95 (dd, 1H), 7.3 (s, 1H), 7.38 (s, 1H), 7.45 (d, 1H),7.6 (s, 1H), 8.5 (s, 1H)

MS-ESI: 463 [MH]⁺

Elemental analysis Found C 67.2 H 6.5 N 12.1 C₂₆H₃₀N₄O₄ Requires C 67.5H 6.5 N 12.1%

EXAMPLE 149

Using an analogous procedure to that described in Example 124,7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (2.3 g, 7.16mmol), (prepared as described in Example 49), was reacted with(N-methyl-N-tert-butoxycarbonyl)ethanolamine (1.51 g, 8.6 mmol) to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline(1.93 g, 56%).

¹H NMR Spectrum: (DMSOd₆) 1.4 (s, 9H), 2.4 (s, 3H), 2.90 (s, 3H), 3.65(t, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.15 (s, 1H), 6.8 (dd, 1H), 7.28 (s,1H), 7.35 (d, 1H), 7.42 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H);

MS-ESI: 479 [MH]³⁰

Elemental analysis Found C 65.0 H 6.4 N 11.7 C₂₆H₃₀N₄O₅S Requires C 65.3H 6.3 N 11.7%

EXAMPLE 150

A solution of6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline(550 mg, 1.15 mmol), (prepared as described in Example 149), inmethylene chloride (10 ml) containing TFA (12 ml) was stirred for 3hours at ambient temperature. After removal of the volatiles undervacuum, the residue was partitioned between methylene chloride andsodium hydrogen carbonate. The pH of the aqueous layer was adjusted to11 with 2N sodium hydroxide. The organic layer was separated, washedwith water, brine, dried (MgSO₄) and evaporated. The residue wastriturated with ether, filtered and dried under vacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline(356 mg, 82%).

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H), 2.5 (s, 3H), 2.9 (t, 2H), 4.0 (s,3H), 4.25 (t, 2H), 6.25 (s, 1H), 6.9 (dd, 1H), 7.25 (s, 1H), 7.3 (d,1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H), 11.0 (s, 1H)

MS-ESI: 379 [MH]+

Elemental analysis Found C 64.6 H 5.8 N 14.2 C₂₁H₂₂N₄O_(3 0.7 H) ₂ORequires C 64.5 H 6.0 N 14.3%

EXAMPLE 151

A mixture of6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(419 mg, 1 mmol), (prepared as described in Example 70), in DMF (6 ml)containing chloroacetonitrile (114 mg, 1.5 mmol), potassium carbonate(346 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) was stirred atambient temperature overnight. The mixture was poured into water and theprecipitate was filtered, washed with water and dried under vacuum. Theresidue was purified by column chromatography, eluting with methylenechloride, followed by methylene chloride/methanol (98/2 and 95/5). Afterremoval of the solvent under vacuum, the residue was triturated withether, filtered, washed with ether and dried under vacuum to give7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(304 mg, 66%).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.6–1.8 (m, 2H), 2.05–2.2 (d, 2H),2.2–2.3 (m, 1H), 2.45 (s, 3H), 3.2 (t, 2H), 3.65 (d, 2H), 4.1 (s, 3H),4.22 (d, 2H), 4.6 (s, 2H), 6.2 (s, 0.5H, partially exchanged), 6.9 (dd,1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H)

MS-ESI: 458 [MH]⁺

Elemental analysis Found C 67.6 H 6.1 N 15.2 C₂₆H₂₇N₅O₃ 0.2 H₂O RequiresC 67.7 H 6.0 N 15.2%

EXAMPLE 152

A mixture of4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(360 mg, 1.00 mmol), potassium carbonate (215 mg, 1.56 mmol) and5-hydroxyindole (147 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100°C. for 5 hours and allowed to cool to ambient temperature. The solventwas removed by evaporation and the residue purified by silica columnchromatography eluting with methanol (2.5 to 5%) in dichloromethane. Theresulting solid was recrystallised from ethyl acetate, filtered andwashed with diethyl ether to give4-(indol-5-yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(77 mg, 17%).

¹H NMR Spectrum: (DMSOd₆) 2.07 (m, 2H), 2.78 (s, 3H), 2.87 (s, 3H), 3.25(t, 2H), 3.97 (s, 3H), 4.23 (t, 2H), 6.43 (br s, 1H), 6.96 (dd, 1H),7.32 (s, 1H), 7.41 (m, 3H), 7.59 (d, 1H), 8.48 (s, 1H) and 11.17 (s, 1H)

MS (ESI): 457 (MH)⁺

Elemental analysis Found C 57.5 H 5.3 N 12.0 C₂₂H₂₄N₄O₅S Requires C 57.9H 5.3 N 12.3%

The starting material was prepared as follows:

Using an analogous procedure to that described for the synthesis of thestarting material in Example 5,4-(4-bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was made in asimilar way to4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline using4-bromo-2-fluorophenol instead of 4-chloro-2-fluorophenol.

A mixture of 4-(4-bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline(9.64 g, 26.4 mmol) and triphenylphosphine (20.9 g, 79.8 mmol) indichloromethane (240 ml) was stirred under nitrogen, at ambienttemperature for 30 minutes. 3-(N-tertButoxycarbonyl)-propanolamine (6.26g, 35.8 mmol) was added followed by diethyl azodicarboxylate (12.4 ml,13.7 g, 78.7 mmol). The reaction mixture was stirred for 2 hours. Thesolvent was then removed by evaporation and the residue taken up inacetonitrile (250 ml). The solution was concentrated to half theoriginal volume and cooled. The resulting crystalline solid wasfiltered, washed with ether and dried to give4-(4-bromo-2-fluorophenoxy)-7-(3-(N-tertbutoxycarbonylamino)propoxy)-6-methoxyquinazoline(10.0 g, 73%).

¹H NMR Spectrum: (DMSOd₆) 1.37 (s, 9H), 1.94 (t, 2H), 3.13 (q, 2H), 3.97(s, 3H), 4.21 (t, 2H), 6.89 (br s, 1H), 7.38 (s, 1H), 7.43–7.53 (m, 2H),7.57 (s, 1H), 7.78 (dd, 1H) and 8.55 (s, 1H)

MS (ESI): 522 (MH)⁺

Elemental analysis Found C 52.1 H 4.7 N 7.9 C₂₃H₂₅N₃BrFO₅ Requires C52.3 H 4.9 N 8.0%

4-(4-Bromo-2-fluorophenoxy)-7-(3-(N-tertbutoxycarbonylamino)propoxy)-6-methoxyquinazoline(5.46 g, 0.5 mmol) was taken up in trifluoroacetic acid (75 ml) andheated at 85° C. for 1.5 hours. The solution was allowed to cool and theexcess trifluoroacetic acid removed by evaporation. The residue was thentreated with aqueous ammonia (0.88) solution, extracted withdichloromethane (3×150 ml) and filtered through phase separating paper.The solvent was removed by evaporation to give7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline(4.42 g, 100%).

¹H NMR Spectrum: (DMSOd₆) 1.87 (m, 2H), 2.73 (t, 2H), 3.98 (s, 3H), 4.26(t, 2H), 7.40 (s, 1H), 7.50 (m, 2H), 7.55 (s, 1H), 7.78 (dd, 1H) and8.55 (s, 1H)

MS (ESI): 422 (MH)⁺

A solution of7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline(2.71 g, 6.4 mmol) and triethylamine (1.1 ml, 0.80 g, 7.9 mmol) indichloromethane (15 ml) was treated with a solution of methanesulphonylchloride (0.53 ml, 0.79 g, 6.9 mmol) in dichloromethane (10 ml) andstirred at ambient temperature, under nitrogen for 18 hours. Thedichloromethane was then removed by evaporation and THF (4 ml) added.The resulting solution was treated with saturated aqueous sodiumhydrogen carbonate solution (to pH 8), stirred vigorously for 30 minutesand the precipitate filtered, washed with water and dried to give4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline(2.98 g, 93%).

¹H NMR Spectrum: (DMSOd₆) 2.01 (m, 2H), 2.90 (s, 3H), 3.15 (t, 2H), 3.96(s, 3H), 4.25 (t, 2H), 7.06 (s, 1H), 7.40 (s, 1H), 7.49 (m, 2H), 7.56(s, 1H), 7.78 (dd, 1H) and 8.54 (s, 1H)

MS (ESI): 500/502 (MH)⁺

4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline(1.0 g, 2 mmol) was taken up in DMF (10 ml), treated with sodium hydride(60% dispersion in mineral oil, 0.11 g, 2.7 mmol) and stirred, undernitrogen for 30 minutes. Methyl iodide (0.16 ml, 2.6 mmol) was added andthe mixture stirred for 18 hours. The solvent was removed by evaporationand the residue taken up in water and extracted with dichloromethane(3×30 ml). The organic solution was then washed with water, brine, dried(MgSO₄) and evaporated to dryness. The crude product was purified bysilica column chromatography eluting with methanol (2.5 to 5%) indichloromethane to give4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylN-methylsulphonylamino) propoxy)quinazoline (0.86 g, 83%).

¹H NMR Spectrum: (DMSOd₆) 2.06 (m, 2H), 2.78 (s, 3H), 2.87 (s, 3H), 3.24(t, 2H), 3.97 (s, 3H), 4.23 (t, 2H), 7.39 (s, 1H), 7.48 (m, 2H), 7.55(s, 1H), 7.78 (dd, 1H) and 8.54 (s, 1H)

MS (ESI): 514/516 (MH)⁺

4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylN-methylsulphonylamino)propoxy)quinazoline (4.70 g, 9.1 mmol) wasdissolved in 2N aqueous hydrochloric acid solution (85 ml) and heated atreflux for 1 hour. After cooling, the solution was carefully poured intosaturated aqueous sodium hydrogen carbonate solution (to pH8) andstirred vigorously for 30 minutes. The resulting precipitate wasfiltered and dried. The filter cake was then taken up as a suspension inacetone, filtered, washed with diethyl ether and dried to give6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-one(3.23 g, 88%).

¹H NMR Spectrum: (DMSOd₆) 2.02 (m, 2H), 2.77 (s, 3H), 2.86 (s, 3H), 3.22(t, 2H), 3.86 (s, 3H), 4.13 (t, 2H), 7.09 (s, 1H), 7.42 (s, 1H), 7.95(s, 1H) and 12.02 (s, 1H)

MS (ESI): 342 (MH)⁺

6-Methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-one(2.24 g, 6.6 mmol) was taken up in thionyl chloride (25 ml) and treatedwith DMF (5 drops). The resulting solution was then heated at reflux for1 hour followed by cooling to ambient temperature. The excess thionylchloride was removed by evaporation followed by azeotroping with toluene(3×). The residue was basified with saturated aqueous sodium hydrogencarbonate solution (to pH8) and extracted twice with ethyl acetate. Theorganic solution was washed with water, brine, dried (MgSO₄) andevaporated to dryness to give4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(1.90 g, 80%).

¹H NMR Spectrum: (DMSOd₆) 2.08 (m, 2H), 2.78 (s, 3H), 2.88 (s, 3H), 3.24(t, 2H), 3.98 (s, 3H), 4.26 (t, 2H), 7.37 (s, 1H), 7.42 (s, 1H) and 8.86(s, 1H)

MS (ESI): 360(MH)⁺

EXAMPLE 153

A mixture of4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(360 mg, 1.00 mm ol), (prepared as described for the starting materialin Example 152), potassium carbonate (215 mg, 1.56 mmol) and5-hydroxy-2-methylindole (162 mg, 1.10 mmol) in DMF (8.0 ml) was stirredat 100° C. for 5 hours and allowed to cool to ambient temperature. Thesolvent was removed by evaporation and the residue was purified bysilica column chromatography eluting with methanol (2.5 to 5%) indichloromethane. The resulting solid was recrystallised from ethylacetate, filtered and washed with diethyl ether to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(166 mg, 35%).

¹H NMR Spectrum: (DMSOd₆) 2.06 (m, 2H), 2.38 (s, 3H), 2.79 (s, 3H), 2.89(s, 3H), 3.24 (t, 2H), 3.96 (s, 3H), 4.21 (t, 2H), 6.11 (br s, 1H), 6.87(dd, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.35 (s, 1H), 7.57 (s, 1H), 8.46(s, 1H) and 10.98 (s, 1H)

MS (ESI): 471 (MH)⁺

Elemental analysis Found C 58.3 H 5.6 N 11.7 C₂₃H₂₆N₄O₅S Requires C 58.7H 5.6 N 11.9%

EXAMPLE 154

A mixture of4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(150 mg, 0.42 mmol), (prepared as described for the starting material inExample 152), potassium carbonate (90 mg, 0.63 mmol) and7hydroxyquinoline (67 mg, 0.46 mmol) in DMF (5.0 ml) was stirred at 100°C. for 2 hours and allowed to cool to ambient temperature. The solventwas removed by evaporation and the residue taken up in 2N. aqueoussodium hydroxide solution. The precipitate was filtered off, dried,taken up in dichloromethane and the solution filtered through phaseseparating paper. The filtrate was then evaporated to dryness. Theresulting solid was recrystallised from acetonitrile, filtered andwashed with diethyl ether to give6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(quinolin-7-yloxy)quinazoline(122 mg, 63%).

¹H NMR Spectrum: (DMSOd₆) 2.09 (m, 2H), 2.79 (s, 3H), 2.90 (s, 3H), 3.26(t, 2H), 3.99 (s, 3H), 4.26 (t, 2H), 7.39 (s, 1H), 7.54 (dd, 1H), 7.56(dd, 1H), 7.60 (s, 1H), 7.91 (d, 1H), 8.09 (d, 1H), 8.44 (d, 1H), 8.55(s, 1H) and 8.93 (dd, 1H)

MS (ESI): 469 (MH)⁺

Elemental analysis Found C 58.6 H 5.1 N 11.9 C₂₃H₂₄N₄O₅S Requires C 59.0H 5.2 N 12.0%

EXAMPLE 155

A mixture of4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(150 mg, 0.42 mmol), (prepared as described for the starting material inExample 152), potassium carbonate (90 mg, 0.63 mmol) and7-hydroxy-4-methylquinoline (71 mg, 0.46 mmol), (Chem. Berich. 1967,100, 2077), in DMF (5.0 ml) was stirred at 100° C. for 2 hours andallowed to cool to ambient temperature. The DMF solvent was removed byevaporation and the residue was taken up in 2N aqueous sodium hydroxidesolution. The precipitate was filtered off, dried, taken up indichloromethane and then filtered through phase separating paper. Thesolution was then evaporated to dryness. The resulting solid wasrecrystallised from acetonitrile, filtered and washed with diethyl etherto give6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4(4-methylquinolin-7-yloxy)quinazoline(84 mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 2.09 (m, 2H), 2.71 (s, 3H), 2.79 (s, 3H), 2.89(s, 3H), 3.25 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 7.37 (s, 1H), 7.38(d, 1H), 7.61 (dd, 1H), 7.63 (s, 1H), 7.89 (d, 1H), 8.20 (d, 1H), 8.54(s, 1H) and 8.76 (d, 1H)

MS (ESI): 483 (MH)⁺

Elemental analysis Found C 59.1 H 5.3 N 11.5 C₂₄H₂₆N₄O₅S Requires C 59.1H 5.0 N 12.0%

EXAMPLE 156

A mixture of(R,S)4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(90 mg, 0.28 mmol), (prepared as described for the starting material inExample 7), potassium carbonate (60 mg, 0.44 mmol) and7-hydroxy-4-trifluoromethylquinoline (65 mg, 0.31 mmol), (prepared as inUkr. Khilm. Zh. (Russ. Ed) Vol. 59, No. 4, pp. 408–411, 1993), in DMF (2ml) was stirred at 100° C. for 6 hours and then allowed to cool toambient temperature. The DMF solvent was removed by evaporation, theresidue was taken up in methanol/dichloromethane (1/1) and pre-absorbedonto silica. The crude mixture was purified by silica columnchromatography eluting with dichloromethane/methanol/0.880 aqueousammonia (95/5/1) and the product recrystallised from acetonitrile togive(R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(4-trifluoromethylquinolin-7-yloxy)quinazoline(58 mg, 42%).

¹H NMR Spectrum: (DMSOd₆ 100° C.) 1.24 (m, 1H), 1.59 (m, 1H), 1.70 (m,1H), 1.83 (m, 1H), 2.05 (m, 2H), 2.17 (m, 1H), 2.24 (s, 3H), 2.64 (dt,1H), 2.84 (dd, 1H), 4.05 (s, 3H), 4.18 (d, 2H), 7.43 (s, 1H), 7.69 (s,1H), 7.87 (dd, 1H), 7.96 (d, 1H), 8.18 (s, 1H), 8.25 (dd, 1H), 8.59 (s,1H) and 9.16 (d, 1H)

MS (ESI): 499 (MH)⁺

Elemental analysis Found C 62.2 H 5.1 N 11.0 C₂₆H₂₅N₄F₃O₃ Requires C62.6 H 5.1 N 11.2%

EXAMPLE 157

A mixture of(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(150 mg, 0.46 mmol), (prepared as described for the starting material inExample 7), potassium carbonate (106 mg, 0.77 mmol) and3-fluoro-7-hydroxyquinoline (119 mg, 0.73 mmol) in DMF (5 ml) wasstirred at 100° C. for 2 hours and then allowed to cool to ambienttemperature. The solvent was removed by evaporation and the residuetreated with 1.0 N aqueous sodium hydroxide solution (30 ml) thenallowed to stir for 30 minutes. The crude solid was collected byfiltration and washed with water. The resultant solid was dissolved indichloromethane and filtered through phase separating paper. The solventwas removed by evaporation and the solid residue was recrystallised fromacetonitrile to give(R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(83 mg, 40%).

¹H NMR Spectrum: (DMSOd₆) 1.11 (m, 1H), 1.50 (m, 1H), 1.64 (m, 1H), 1.84(m, 3H), 2.10 (m, 1H), 2.15 (s, 3H), 2.62 (d, 1H), 2.83 (d, 1H), 4.00(s, 3H), 4.08 (d, 2H), 7.38 (s, 1H), 7.62 (s, 1H), 7.68 (dd, 1H), 7.97(d, 1H), 8.10 (d, 1H), 8.34 (dd, 1H), 8.54 (s, 1H) and 8.97 (d, 1H)

MS (ESI): 449 (MH)⁺

Elemental analysis Found C 66.2 H 5.6 N 12.3 C₂₅H₂₅N₄FO₃ 0.2 H₂ORequires C 66.4 H 5.7 N 12.4%

The starting material, 3-fluoro-7-hydroxyquinoline was prepared asfollows:

3-Fluoro-7-methoxyquinol-2(1H)-one (300 mg, 1.55 mmol), (prepared as inTetrahedron, Vol. 52, No. 9, pp. 3223–3228, 1996), was dissolved inthionyl chloride (3 ml), treated with DMF (1 drop) and heated at refluxfor 1 hour. The excess thionyl chloride was removed by evaporation andthe residue azeotroped with toluene (3×). The residue was basified topH8 with saturated aqueous sodium hydrogen carbonate solution andextracted with ethyl acetate (3×20 ml). The organic solution was washedwith water and brine then dried (MgSO₄) and evaporated to dryness togive 2-chloro-3-fluoro-7-methoxyquinoline (320 mg, 97%).

¹H NMR Spectrum: (CDCl₃) 3.95 (s, 3H), 7.25 (dd, 1H), 7.37 (d, 1H), 7.67(d, 1H) and 7.78 (d, 1H)

MS (ESI): 212 (MH)⁺

A mixture of 2-chloro-3-fluoro-7-methoxyquinoline (310 mg, 1.47 mmol),triethylamine (310 mg, 0.4 ml, 3.07 mmol) and 10% palladium on activatedcharcoal (50 mg) in dry ethanol (5 ml) was stirred under hydrogen gas atambient temperature for 24 hours. The mixture was then filtered throughcelite. The celite was washed with methanol and the solvent was removedby evaporation from the combined filtrates. The crude material waspurified by chromatography on silica, eluting with 10% ethyl acetate inisohexane to give 3-fluoro-7-methoxyquinoline (130 mg, 54%).

¹H NMR Spectrum: (CDCl₃) 3.96 (s, 3H), 7.24 (dd, 1H), 7.44 (d, 1H), 7.66(d, 1H) and 7.73 (dd, 1H) and 8.76 (d, 1H)

MS (ESI): 178 (MH)⁺

3-Fluoro-7-methoxyquinoline (130 mg, 0.74 mmol) was taken up indichloromethane (2 ml) under nitrogen and treated with boron tribromide(4 ml of a 11.0M solution of in dichloromethane). The reaction mixturewas stirred for 24 hours at ambient temperature followed by quenchingthe reaction by the slow addition of excess methanol. The solution wasstirred for a further 2 hours and evaporated to dryness to give3-fluoro-7-hydroxyquinoline which was used without further purification.

MS (ESI): 164 (MH)⁺

EXAMPLE 158

A mixture of(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(240 mg, 0.75 mmol), (prepared as described for the starting material inExample 7), potassium carbonate (160 mg, 1.16 mmol) and3-fluoro-7-hydroxy-2methylquinoline (150 mg, 0.85 mmol) in DMF (6 ml)was stirred at 100° C. for 5 hours and then allowed to cool to ambienttemperature. The solvent was removed by evaporation, then the residuewas treated with water and 1.0 N aqueous sodium hydroxide solution (30ml) then allowed to stir for 30 minutes. The crude solid was collectedby filtration and washed with water. The resulting solid was dissolvedin dichloromethane and filtered through phase separating paper. Thesolvent was removed by evaporation to give a solid residue which wasrecrystallised from acetonitrile to give4-(3-fluoro-2-methylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline(71 mg, 21%).

¹H NMR Spectrum: (DMSOd₆) 1.11 (m, 1H), 1.68 (m, 5H), 2.10 (m, 1H), 2.20(s, 3H), 2.64 (m, 4H), 2.87 (d, 1H), 3.98 (s, 3H), 4.09 (d, 2H), 7.37(s, 1H), 7.57 (dd, 1H), 7.60 (s, 1H), 7.86 (d, 1H), 8.02 (d, 1H), 8.20(d, 1H) and 8.53 (s, 1H)

MS (ESI): 463 (MH)⁺

Elemental analysis Found C 66.4 H 6.1 N 11.8 C₂₆H₂₇N₄FO₃ 0.4 H₂ORequires C 66.5 H 6.0 N 11.9%

The starting material was prepared as follows:

2-Chloro-3-fluoro-7-methoxyquinoline (210 mg, 1 mmol), (prepared asdescribed for the starting material in Example 157), in anhydrous THF (1ml) was added to a mixture of copper(I)bromide (570 mg, 4.0 mmol) andmethylmagnesium bromide (3.0M solution in diethyl ether, 2.7 ml, 8 mmol)in anhydrous THF (20 ml) at −78° C. The mixture was stirred for 1 hourat −78° C., allowed to warm to ambient temperature and then stirred fora further 18 hours. Saturated aqueous ammonium chloride solution and 5Naqueous sodium hydroxide solution (pH 12) were added and the productextracted with ethyl acetate (3×). The organic solution was washed withwater, brine, dried (MgSO₄) and evaporated to dryness to yield3-fluoro-7-methoxy-2-methylquinoline (0.17 g, 91%).

¹H NMR Spectrum: (CDCl₃) 2.70 (d, 3H), 3.94 (s, 3H), 7.17 (dd, 1H), 7.37(d, 1H) and 7.61 (m, 2H)

MS (ESI): 192 (MH)⁺

3-Fluoro-7-methoxy-2-methylquinoline (0.16 g, 0.85 mmol) was taken up indichloromethane (4 ml) under nitrogen and treated with boron tribromidesolution (4 ml of a 11.0M solution in dichloromethane, 4.0 mmol). Thereaction was stirred for 24 hours at ambient temperature followed by theslow addition of excess methanol. The solution was stirred for a further2 hours and then evaporated to dryness to give3-fluoro-7-hydroxy-2-methylquinoline which was used without furtherpurification.

MS (ESI): 178 (MH)⁺

EXAMPLE 159

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (400mg, 1.19 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (255 mg, 1.84 mmol) and7-hydroxyquinoline (180 mg, 1.32 mmol) in DMF (10 ml) was stirred at100° C. for 4 hours and then allowed to cool to ambient temperature. Theresulting mixture was treated with 1.0 N aqueous sodium hydroxidesolution (30 ml) and allowed to stir for 1 hour. The crude solid wascollected by filtration and washed with water. The resulting solid wasdissolved in dichloromethane and filtered through phase separatingpaper. The solvent was removed by evaporation to give a solid residuewhich was recrystallised from acetonitrile to give6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline (0.27g, 52%).

¹H NMR Spectrum: (DMSOd₆) 1.37 (m, 2H), 1.51 (m, 4H), 1.95 (m, 2H), 2.32(m, 4H), 2.42 (t, 2H), 3.98 (s, 3H), 4.23 (t, 2H), 7.38 (s, 1H), 7.56(m, 2H), 7.62 (s, 1H), 7.91 (d, 1H), 8.09 (d, 1H), 8.44 (d, 1H), 8.54(s, 1H) and 8.91 (dd, 1H)

MS (ESI): 445 (MH)⁺

Elemental analysis Found C 70.9 H 6.3 N 12.7 C₂₆H₂₈N₄O₃ Requires C 70.3H 6.3 N 12.6%

EXAMPLE 160

A mixture of4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(360 mg, 1.00 mmol), (prepared as described for the starting material inExample 152), potassium carbonate (215 mg, 1.56 mmol) and2,3-dimethyl-5-hydroxyindole (177 mg, 1.10 mmol), (Arch. Pharm. 1972,305, 159), in DMF (8.0 ml) was stirred at 100° C. for 5 hours andallowed to cool to ambient temperature. The solvent was removed byevaporation and the residue purified by silica column chromatographyeluting with methanol (2.5%) in dichloromethane. The resulting solid wasrecrystallised from tertbutyl methyl ether/acetonitrile, filtered andwashed with diethyl ether to give4-(2,3-dimethylindol-5yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(201 mg, 42%).

¹H NMR Spectrum: (DMSOd₆) 2.07 (m, 2H), 2.12 (s, 3H), 2.31 (s, 3H), 2.79(s, 3H), 2.89 (s, 3H), 3.25 (t, 2H), 3.97 (s, 3H), 4.23 (t, 2H), 6.86(dd, 1H), 7.20 (d, 1H), 7.25 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.46(s, 1H) and 11.17 (s, 1H)

MS (ESI): 485 (MH)⁺

Elemental analysis Found C 59.5 H 5.8 N 11.4 C₂₄H₂₈N₄O₅S Requires C 59.5H 5.8 N 11.6%

EXAMPLE 161

A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(322 mg, 1.00 mmol), (prepared as described in Example 49), potassiumcarbonate (414 mg, 3.00 mmol) and epibromohydrin (274 mg, 2.00 mmol) inDMF (7.0 ml) was stirred at 60° C. for 2 hours and allowed to cool toambient temperature. The solvent was removed by evaporation and theresidue taken up in dichloromethane (10 ml). An aliquot (5 ml) of thissolution was treated with morpholine (48 ul, 0.6 mmol) and stirred for24 hours at ambient temperature. The solvent was removed by evaporation,treated with water and stirred vigorously for 30 minutes. Theprecipitate was filtered, washed with water and dried. The resultantsolid was stirred as a suspension in acetone, filtered, washed withdiethyl ether and dried to give7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(127 mg, 27%).

¹H NMR Spectrum: (DMSOd₆) 2.38 (s, 3H), 2.45 (m, 6H), 3.57 (t, 4H), 3.95(s, 3H), 4.03–4.14 (m, 2H), 4.23 (m, 1H), 4.95 (s, 1H), 6.12 (s, 1H),6.86 (dd, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 7.57 (s, 1H),8.47 (s, 1H) and 10.98 (s, 1H)

MS (ESI): 465 (MH)⁺

Elemental analysis Found C 62.7 H 5.9 N 11.5 C₂₅H₂₈N₄O₅0.7H₂O Requires C62.9 H 6.2 N 11.7%

EXAMPLE 162

A mixture of7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100mg, 0.27 mmol) and piperidine (79ul, 0.8 mmol) in DMF (4 ml) was heatedat 70° C. for 24 hours. The solvent was removed by evaporation and theresidue was recrystallised from acetonitrile. The solid was filtered,washed with diethyl ether and dried to give7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5yloxy)quinazoline(80 mg, 65%).

¹H NMR Spectrum: (DMSOd₆) 1.35 (m, 2H), 1.51 (m, 4H), 2.39 (m, 9H), 3.96(s, 3H), 4.08 (m, 2H), 4.21 (dd, 1H), 4.86 (br s, 1H), 6.11 (s, 1H),6.87 (dd, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 7.56 (s, 1H),8.45 (s, 1H) and 10.98 (s, 1H)

MS (ESI): 464 (MH)⁺

Elemental analysis Found C 66.2 H 6.4 N 11.9 C₂₆H₃₀N₄O₄0.4H₂O Requires C66.5 H 6.6 N 11.9%

The starting material was prepared as follows:

A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(1.89 g, 5.90 mmol), (prepared as described in Example 49), potassiumcarbonate (2.43 g, 17.6 mmol) and epibromohydrin (1.61 g, 11.7 mmol) inDMF (40 ml) was stirred at 60° C. for 2 hours and allowed to cool toambient temperature. The insoluble inorganic material was removed byfiltration and the solvent was removed by evaporation. The residue wastriturated with diethyl ether, filtered, washed with further diethylether and dried to give7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(1.97 g, 89%).

¹H NMR Spectrum: (DMSOd₆) 2.38 (s, 3H), 2.76 (m, 1H), 2.90 (t, 1H), 3.43(m, 1H), 3.97 (s, 3H), 4.04 (m, 1H), 4.57 (dd, 1H), 6.11 (s, 1H), 6.86(dd, 1H), 7.27 (m, 2H), 7.38 (s, 1H), 7.59 (s, 1H), 8.46 (s, 1H) and10.92 (s, 1H)

MS (ESI): 378 (MH)⁺

EXAMPLE 163

A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the startingmaterial in Example 162), and pyrrolidine (67 ul, 0.8 mmol) in DMF (4ml) was heated at 70° C. for 24 hours. The solvent was removed byevaporation and the residue purified by silica column chromatographyeluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1).The relevant fractions were evaporated to dryness then the residuetreated with a little dichloromethane and dried under high vacuum togive7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(44 mg, 37%) as a white foam.

¹H NMR Spectrum: (DMSOd₆) 1.69 (br s, 4H), 2.38 (s, 3H), 2.50 (m, 6H),3.97 (s, 3H), 4.07 (m, 2H), 4.21 (dd, 1H), 4.96 (br s, 1H), 6.11 (s,1H), 6.86 (dd, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.56 (s,1H), 8.46 (s, 1H) and 10.98 (s, 1H)

MS (ESI): 450 (MH)⁺

Elemental analysis Found C 65.5 H 6.3 N 11.8 C₂₅H₂₈N₄O₄0.4H₂O Requires C65.9 H 6.4 N 12.3%

EXAMPLE 164

A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the startingmaterial in Example 162), and diethylamine (100 ul, 0.8 mmol) in DMF (4ml) was heated at 70° C. for 24 hours. The solvent was removed byevaporation and the residue was purified by silica column chromatographyeluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1).The relevant fractions were evaporated to dryness then the residuetreated with a little dichloromethane and dried under high vacuum togive7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(55 mg, 46%) as a white foam.

¹H NMR Spectrum: (DMSOd₆) 0.96 (t, 6H), 2.38 (s, 3H), 2.52 (m, 6H), 3.96(s, 3H), 3.97 (m, 1H), 4.09 (m, 1H), 4.23 (dd, 1H), 4.84 (br s, 1H),6.12 (s, 1H), 6.88 (dd, 1H), 7.24 (d, 1H), 7.29 (d, 1H), 7.36 (s, 1H),7.56 (s, 1H), 8.45 (s, 1H) and 10.98 (s, 1H)

MS (ESI): 452 (MH)⁺

Elemental analysis Found C 66.2 H 6.7 N 12.4 C₂₅H₃₀N₄O₄ Requires C 66.6H 6.7 N 12.4%

EXAMPLE 165

A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the startingmaterial in Example 162), and N-methylpiperazine (200 ul, 1.8 mmol) inDMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed byevaporation and the residue was recrystallised from acetonitrile. Thesolid was filtered, washed with diethyl ether and dried to give7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(41 mg, 32%).

¹H NMR Spectrum: (DMSOd₆): 2.11 (s, 3H), 2.29 (m, 4H), 2.40 (s, 3H),2.47 (m, 6H), 3.96 (s, 3H), 4.07 (m, 2H), 4.20 (dd, 1H), 4.89 (d, 1H),6.11 (s, 1H), 6.87 (dd, 1H), 7.23 (d, 1H), 7.29 (d, 1H), 7.35 (s, 1H),7.58 (s, 1H), 8.46 (s, 1H) and 10.98 (s, 1H)

MS (ESI): 479 (MH)⁺

Elemental analysis Found C 64.4 H 6.5 N 14.4 C₂₆H₃₁N₅O₄0.3H₂O Requires C64.7 H 6.6 N 14.5%

EXAMPLE 166

A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the startingmaterial in Example 162), and isopropylamine (100 ul, 0.8 mmol) in DMF(4 ml) was heated at 70° C. for 24 hours. The solvent was removed byevaporation and the residue was purified by silica column chromatographyeluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) togive7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4(2-methylindol-5-yloxy)quinazoline(18 mg, 16%).

¹H NMR Spectrum: (DMSOd₆) 1.00 (d, 6H), 2.40 (s, 3H), 2.56–2.78 (m, 3H),3.97 (m, 4H), 4.07–4.28 (m, 2H), 5.04 (m, 1H), 6.12 (s, 1H), 6.88 (dd,1H), 7.22–7.33 (m, 2H), 7.38 (s, 1H), 7.58 (s, 1H), 8.48 (s, 1H) and10.98 (s, 1H)

MS (ESI): 437 (MH)⁺

EXAMPLE 167

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168mg, 0.5 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (276 mg, 2.0 mmol) and5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0 ml)were stirred at 95° C. for 1.5 hours and allowed to cool to ambienttemperature. The reaction mixture was filtered and the filtrateevaporated under vacuum. The residue was purified by silica columnchromatography eluting with dichloromethane/methanol/0.880 aqueousammonia (89/10/1) to give a partially purified oil. This oil was furtherpurified by high performance column chromatography on octadecylsilanereverse phase silica eluting with acetonitrile/water/trifluoroaceticacid (60/39.8/0.2) to give an oil which was dissolved in dichloromethaneand washed with saturated aqueous sodium hydrogen carbonate solution.The dichloromethane layer was evaporated to give6-methoxy-7-(3-piperidinopropoxy)-4(6-trifluoromethylindol-5-yloxy)quinazoline(62 mg, 25%).

¹H NMR Spectrum: (DMSOd₆) 1.45 (m, 2H), 1.60 (m, 4H), 2.13 (m, 2H), 2.44(m, 4H), 2.56 (m, 2H), 4.04 (s, 3H), 4.27 (t, 2H), 6.63 (br s, 1H), 7.33(s, 1H), 7.40 (t, 1H), 7.61 (s, 1H), 7.67 (s, 1H), 7.75 (s, 1H) and 8.60(m, 2H)

MS (ESI): 501 (MH)⁺

Elemental analysis Found C 62.0 H 5.6 N 10.6 C₂₆H₂₇F₃N₄O₃ 0.35 H₂O,Requires C 61.6 H 5.5 N 11.0%

The starting material was prepared as follows:

Sodium hydride (1.8 g, of a 60% dispersion in oil, 45 mmol) was added inportions to a stirred solution of benzyl alcohol (10.8 g, 100 mmol) inDMA (100 ml) with vigorous stirring under an atmosphere of nitrogen atambient temperature. After warming to 45° C. for 30 minutes the mixturewas cooled to ambient temperature and added dropwise to a stirredsolution of 2-chloro-5-nitro-trifluoromethylbenzene (11.3 g, 50 mmol) inDMA (30 ml), keeping the temperature below 110° C. The mixture wasstirred at 25° C. for 1 hour, then acidified with acetic acid andevaporated to give a yellow solid. The residue was dissolved indichloromethane, washed with water then dried (MgSO₄), and evaporated.The residue was suspended in a mixture of hexane (70 ml) and diethylether (10 ml) and the resulting solid filtered off to give2-benzyloxy-5-nitro-trifluoromethylbenzene (6.6 g, 49%).

¹H NMR Spectrum: (CDCl₃) 5.33 (s, 2H), 7.13 (d, 1H), 7.31–7.43 (m, 5H),8.35 (dd, 1H), 8.52 (d, 1H)

Potassium tert-butoxide (3.94 g, 35.4 mmol) was dissolved in anhydrousDMF (15 ml) and a mixture of 2-benzyloxy-5-nitro-trifluoromethylbenzene(3.5 g, 16.1 mmol) and 4-chlorophenylacetonitrile (2.96 g, 17.7 mmol) inDMF (20 ml) was added over 30 minutes keeping the temperature at −15C.The mixture was stirred at −10° C. for 1 hour, then poured into 1Mhydrochloric acid (150 ml) and the product extracted withdichloromethane (2×100 ml). The organic extracts were dried (MgSO₄) andpurified by silica column chromatography eluting withdichloromethane/hexane (1/1) to give5-benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (5.2 g, 77%).

¹H NMR Spectrum: (CDCl₃) 4.30 (s, 2H), 5.38 (s, 2H), 7.25 (s, 1H),7.33–7.50 (m, 5H) and 8.51 (s, 1H)

MS (ESI): 335 (M−H)⁻

5-Benzyloxy-2-nitro-4(trifluoromethyl)phenylacetonitrile (2.22 g, 6.6mmol) was dissolved in ethanol (45 ml), water (5 ml) and acetic acid(0.32 ml) then hydrogenated with 10% palladium on carbon at 1 atmospherepressure for 2 hours. The catalyst was filtered off and filtrateevaporated to give 5-hydroxy-6-trifluoromethylindole (1.12 g, 84%).

¹H NMR Spectrum: (CDCl₃) 4.48 (s, 1H), 6.48 (m, 1H), 7.14 (s, 1H), 7.32(t, 1H), 7.57 (s, 1H) and 8.20 (br s, 1H)

MS (ESI): 200 (M-H)⁻

EXAMPLE 168

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200mg, 0.6 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (248 mg, 1.8 mmol) and5-hydroxy-6-methoxyindole (127 mg, 0.78 mmol) in DMA (4.0 ml) wasstirred at 95° C. for 2.5 hours. The reaction mixture was allowed tocool to ambient temperature, filtered and the filtrate evaporated undervacuum. The residue was purified by silica column chromatography elutingwith dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) and theresulting oil triturated with diethyl ether to give4-(6-methoxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(106 mg, 38%).

¹H NMR Spectrum: (DMSOd₆) 1.38 (m, 2H), 1.47 (m, 4H), 1.95 (m, 2H), 2.32(m, 4H), 2.40 (m, 2H), 3.66 (3H, s), 3.97 (s, 3H), 4.28 (t, 2H), 6.35(br s, 1H), 7.06 (s, 1H), 7.24 (t, 1H), 7.34 (s, 1H), 7.36 (s, 1H), 7.55(s, 1H) and 8.41 (s, 1H)

MS (ESI): 463 (MH)⁺

Elemental analysis Found C 65.2 H 6.8 N 11.2 C₂₆H₃₀N₄O₄ 1.0 H₂O, 0.3Requires C 64.9 H 7.0 N 11.1% diethyl ether

The 5-hydroxy-6-methoxyindole starting material was made as follows:

5-Benzyloxy-6-methoxyindole (253 mg, 11.0 mmol) was hydrogenated at 1atmosphere pressure in methanol (10 ml) with 10% palladium on carbon (50mg) for 2 hours at 25° C. The catalyst was filtered off and the filtrateevaporated to give 5-hydroxy-6-methoxylindole (141 mg, 87%).

¹H NMR Spectrum: (CDCl₃) 3.92 (s, 3H), 5.40 (s, 1H), 6.42 (br s, 1H),6.87 (s, 1H), 7.07 (m, 1H), 7.13 (s, 1H), 7.93 (br s, 1H)

MS (ESI): 162 (M-H)⁻

EXAMPLE 169

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200mg, 0.595 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (411 mg, 2.98 mmol) and 4-hydroxyindole(103 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hoursand allowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated to give a solid residue. Theresidue was purified by silica column chromatography, with gradientelution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia togive 4-(indolyloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (131mg, 51%).

¹H NMR Spectrum: (DMSOd₆) 1.39 (m, 2H), 1.50 (m, 4H), 1.98 (t, 2H), 2.35(m, 4H), 2.40 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 6.10 (t, 1H), 6.90(d, 1H), 7.15 (t, 1H), 7.30 (t, 1H), 7.35 (d, 1H), 7.38 (s, 1H), 7.62(s, 1H), 8.45 (s, 1H) and 11.29 (s, 1H)

MS (ESI): 433 (MH)⁺

m.p. 80–82° C.

EXAMPLE 170

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200mg, 0.595 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (411 mg, 2.98 mmol) and3-hydroxycarbazole (142 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at85° C. for 3 hours then allowed to cool to ambient temperature. Thereaction mixture was filtered and the filtrate evaporated to give asolid residue. The residue was purified by silica column chromatographywith gradient elution using dichloromethane with 0%, 2%, 4%, 10%methanolic ammonia to give4-(9H-carbazol-3-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(212 mg, 74%).

¹H NMR Spectrum: (DMSOd₆) 1.39 (m, 2H), 1.50 (m, 4H), 2.35 (m, 4H), 2.40(t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 7.05 (dd, 1H), 7.15 (t, 1H), 7.35(t, 1H), 7.38 (s, 1H), 7.40 (s, 1H), 7.50 (d, 1H), 7.60 (s, 1H), 8.10(d, 1H), 8.15 (d, 1H), 8.55 (s, 1H) and 11.33 (s, 1H)

MS (ESI): 483 (MH)⁺

EXAMPLE 171

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (84mg, 0.24 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (162 mg, 1.18 mmol) and ethyl7-chloro-5-hydroxyindole-2-carboxylate (62 mg, 0.26 mmol) in DMA (2.0ml) was stirred at 100° C. for 2 hours and allowed to cool to ambienttemperature. The reaction mixture was filtered and the filtrateevaporated. The residue was purified by silica column chromatographyusing gradient elution dichloromethane with 2.5%, 5%, 10% methanol, thendichloromethane with 2% ammonia) to give4-(7-chloro-2-(ethoxycarbonyl)indol-5-yloxy)-6-(methoxy-7-(3-piperidinopropoxy)quinazoline(78 mg, 63%).

¹H NMR Spectrum: (DMSOd₆) 1.30 (t, 3H), 1.40 (m, 2H), 1.50 (m, 4H), 1.98(t, 2H), 2.35 (m, 4H), 2.40 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 4.30(q, 2H), 7.15 (m, 1H), 7.18 (s, 1H), 7.60 (s, 1H), 8.40 (s, 1H) and12.60 (s, 1H)

MS (ESI): 539 (MH)⁺

Elemental analysis Found C 61.2 H 5.9 N 10.3 C₂₈H₃₁ClN₄O₅ 0.5 H₂ORequires C 61.4 H 5.9 N 10.2%

The starting material was prepared as follows:

2-Chloro-4-methoxyaniline (2.719 g, 14 mmol) was added to 8.0M aqueoushydrochloric acid (15 ml) and the suspension cooled to −5° C. Sodiumnitrite (1.063 g, 15.4 mmol) was added as a solution in water (3 ml).After addition the pH was brought to pH 4–5 by addition of sodiumacetate. In a separate flask, ethyl-α-ethyl acetoacetate (2.18 ml, 15.4mmol) in ethanol (15 ml) at −5° C. was treated with potassium hydroxide(864 mg, 15.4 mmol) in water (3 ml) followed by ice (4 g). The diazoniumsalt prepared initially was then added rapidly to the second solutionand stirred at −5° C. for 4 hours then allowed to warm to ambienttemperature overnight. The mixture was extracted with ethyl acetate(3×100 ml) and the organic solutions dried (MgSO₄), filtered and solventremoved in vacuo to give an orange oil. This oil was dissolved inethanol (35 ml) and the flask fitted with a reflux condenser.Concentrated sulphuric acid (35 ml) was then added dropwise, this causedthe reaction to reflux with no external heating. The solution wasstirred for 1 hour then the solvent removed by evaporation. The residuewas taken up in water then extracted with ethyl acetate (3×100 ml). Theorganic solution was washed with brine, dried (MgSO₄), filtered andevaporated to give a brown oil. The crude oil was purified by silicacolumn chromatography, eluting with dichloromethane to give ethyl7-chloro-5-methoxyindole-2-carboxylate (125 mg, 4%).

¹H NMR Spectrum: (CDCl₃) 1.40 (t, 3H), 3.98 (s, 3H), 4.40 (q, 2H), 6.60(d, 1H), 7.05 (d, 1H), 7.15 (s, 1H) and 9.10 (s, 1H)

MS (ESI): 254 (MH)⁺

To a solution of ethyl 7-chloro-5-methoxyindole-2-carboxylate (82 mg,0.323 mmol) in dichloromethane (5 ml) at −78° C. was added borontribromide (1.07 ml of a 1.0M solution in DCM, 1.07 mmol) and thereaction stirred at −78° C. for 30 minutes then allowed to warm toambient temperature overnight. Water was carefully added and the pHadjusted to pH 6–7 by addition of 2M sodium hydroxide. The mixture wasextracted with ethyl acetate (2×50 ml), and the organic solution washedwith brine, dried (MgSO₄), filtered and evaporated to give ethyl7-chloro-5-hydroxyindole-2-carboxylate (55 mg, 71%) as an orange solid.

¹H NMR Spectrum: (DMSOd₆) 1.38 (t, 3H), 4.35 (q, 2H), 6.60 (d, 1H), 6.95(d, 1H), 7.10 (d, 1H), 9.80 (s, 1H) and 11.80 (s, 1H)

MS (ESI): 238 (MH)³¹

EXAMPLE 172

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.5 g, 4.99mmol), (prepared as described for the starting material in Example 1),potassium carbonate (2.07 g, 15 mmol) and 2,3-dimethyl-5-hydroxyindole(1.21 g, 7.5 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (75 ml) wasstirred at 100° C. for 2 hours and allowed to cool to ambienttemperature. The reaction mixture was filtered and the filtrateevaporated. The solid residue was purified by silica columnchromatography, eluting with 2.5% methanol in dichoromethane to give7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (976 mg,46%).

¹H NMR Spectrum: (CDCl₃) 2.10 (s, 3H), 2.30 (s, 3H), 3.98 (s, 3H), 5.30(s, 2H), 6.85 (dd, 1H), 7.20 (d, 1H), 7.25 (d, 1H), 7.40 (m, 6H), 7.60(s, 1H), 8.40 (s, 1H) and 10.74 (s, 1H)

MS (ESI): 426 (MH)⁺

EXAMPLE 173

A mixture of7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (912 mg,2.14 mmol), (prepared as described in Example 172), di-tert-butyldicarbonate (1.871 g, 8.56 mmol) and 4-dimethylaminopyridine (70 mg, 5mol %) in acetonitrile (40 ml) was stirred at ambient temperatureovernight. The solvent was then evaporated and the residue dissolved inethyl acetate. The organic solution was washed with 2N hydrochloric acidtwice and then with brine. The organic layer was then dried (MgSO₄),filtered and evaporated to give7-benzyloxy-4-(1-tert-butoxycarbonyl-2,3-dimethylindol-5yloxy)-6-methoxyquinazoline(1.108 g, 99%) as a yellow solid.

¹H NMR Spectrum: (CDCl₃) 1.70 (s, 9H), 2.08 (s, 3H), 2.50 (s, 3H), 4.10(s, 3H), 5.35 (s, 2H), 7.15 (dd, 1H), 7.38 (m, 6H), 7.60 (s, 1H), 8.20(d, 1H) and 8.60 (s, 1H)

MS (ESI): 526 (MH)⁺

EXAMPLE 174

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), (prepared as described for the starting material inExample 1), potassium carbonate (106 mg, 0.77 mmol) and2-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperature. Thereaction mixture was treated with 1.0 N aqueous sodium hydroxidesolution (40 ml) and allowed to stir at ambient temperature for a fewminutes. The reaction mixture was extracted 3 times with ethyl acetateand the extracts washed with water and brine. The organic extracts weredried over magnesium sulphate, filtered and the solvent removed byevaporation. The residue was purified by silica column chromatographyeluting with dichloromethane/methanol (95/5) to give a solid which wastriturated with ether, filtered and dried to give6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)-quinazoiine (33mg, 11%).

¹H NMR Spectrum: (DMSOd₆) 1.98 (m, 2H), 2.38 (m, 4H), 2.48 (t, 2H), 3.58(m, 4H), 3.98 (s, 3H), 4.26 (t, 2H), 7.41 (s, 1H), 7.52 (d, 1H), 7.58(s, 1H), 7.64 (t, 1H), 7.78 (m, 1H), 7.88 (d, 1H), 8.06 (d, 1H), 8.56(d, 1H) and 8.57 (s, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis Found C 66.8 H 5.9 N 12.4 C₂₅H₂₆N₄O₄ 0.2 H₂O RequiresC 66.7 H 5.9 N 12.4%

EXAMPLE 175

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225mg, 0.67 mmol), (prepared as described for the starting material inExample 1), potassium carbonate (106 mg, 0.77 mmol) and5-hydroxyquinoline (111 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperature. Thereaction mixture was treated with 1.0 N aqueous sodium hydroxidesolution (40 ml) and allowed to stir at ambient temperature for a fewminutes. The resulting precipitate was filtered off, washed with waterand air dried for a short while. The damp solid was dissolved indichloromethane, filtered through phase separating paper and thefiltrate evaporated under vacuum. The residue was triturated with ether,filtered and dried to give6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-5-yloxy)-quinazoline (178mg, 59%).

¹H NMR Spectrum: (DMSOd₆) 1.98 (m, 2H), 2.39 (m, 4H), 2.48 (t, 2H), 3.59(t, 4H), 4.01 (s, 3H), 4.28 (t, 2H), 7.42, (s, 1H), 7.50 (m, 1H), 7.59(d, 1H), 7.74 (s, 1H), 7.87 (t, 1H), 8.02 (d, 1H), 8.20 (m, 1H), 8.44(s, 1H) and 8.96 (m, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis Found C 66.2 H 5.7 N 12.4 C₂₅H₂₆N₄O₄ 0.4 H₂O RequiresC 66.2 H 6.0 N 12.4%

EXAMPLE 176

A mixture of4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (200mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7 ml) was stirred at 100°C. for 5 hours and allowed to cool to ambient temperature. The reactionmixture was treated with 1.0 N aqueous sodium hydroxide solution (40 ml)and allowed to stir at ambient temperature for a few minutes. Thereaction mixture was extracted 4 times with ethyl acetate and theorganic extracts washed with water and brine. The organic extracts weredried over magnesium sulphate, filtered and the solvent removed byevaporation. The residue was triturated with ether/isohexane, filteredand dried to give6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)4-(quinolin-7-yloxy)quinazoline(102 mg, 39%).

¹H NMR Spectrum: (DMSOd₆) 1.96 (m, 2H), 2.15 (s, 3H), 2.35 (m, 8H), 2.46(t, 2H), 3.99 (s, 3H), 4.24 (t, 2H), 7.39 (s, 1H), 7.56 (m, 1H), 7.61(m, 1H), 7.62 (s, 1H), 7.92 (d, 1H), 8.10 (d, 1H), 8.44 (d, 1H), 8.54(s, 1H) and 8.92 (m, 1H)

MS (ESI): 460 (MH)⁺

Elemental analysis Found C 67.2 H 6.2 N 15.0 C₂₆H₂₉N₅O₃ 0.3 H₂O RequiresC 67.2 H 6.4 N 15.1%

The starting material was prepared as follows:

A solution of 1-(3-hydroxypropyl)-4-methylpiperazine (2.4 g, 15 mmol),(prepared as described for the starting material in Example 133), indichloromethane (60 ml) was treated with triethylamine (4.6 ml, 33 mmol)and p-toluenesulphonyl chloride (3.2 g, 17 mmol) and stirred at ambienttemperature for 2 hours. The solution was washed with saturated aqueoussodium hydrogen carbonate solution followed by water and filteredthrough phase separating paper. The filtrate was evaporated under vacuumto give 3-(4-methyl-piperazin-1-yl)propyl-4-toluene sulphonate as an oilwhich crystallised on standing (3.7 g, 78%).

MS (ESI): 313 (MH)⁺

A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med. Chem. 1977,vol 20, 146–149, 10 g, 0.04 mol) and Gold's reagent (7.4 g, 0.05 mol) indioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodiumacetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) wereadded to the reaction mixture and it was heated for a further 3 hours.The mixture was evaporated, water was added to the residue, the solidwas filtered off, washed with water and dried. Recrystallisation fromacetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7g, 84%).

A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g,0.01 mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred andheated at reflux for 1 hour. The mixture was evaporated and azeotropedwith toluene to give 7-benzyloxy-4-chloro-6-methoxyquinazolinehydrochloride (3.45 g).

4-Chloro-2-fluoro-phenol (264 mg, 1.8 mmol) was added to a solution of7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (506 mg, 1.5mmol) in pyridine (8 ml) and the mixture heated at reflux for 45minutes. The solvent was removed by evaporation and the residuepartitioned between ethyl acetate and water. The organic layer waswashed with 0.1M HCl, water and brine, dried (MgSO₄) and the solventremoved by evaporation. The solid residue was triturated with petroleumether and the crude product collected by filtration and purified byflash chromatography eluting with methylene chloride/ether (9/1) to give7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (474 mg,77%) as a cream solid.

m.p. 179–180° C.

¹H NMR Spectrum: (DMSOd₆) 3.99(s, 3H); 5.36(s, 2H); 7.35–7.5(m, 4H);7.55–7.65(m, 5H); 7.72(d, 1H); 8.6(s, 1H)

MS-ESI: 411 [MH]⁺

Elemental analysis: Found C 63.38 H 4.07 N 6.78 C₂₁H₁₆ClFN₂O₃ 0.06H₂ORequires C 63.64 H 3.93 N 6.73% 0.05CH₂Cl₂

A solution of7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg,1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The mixturewas diluted with toluene and the volatiles removed by evaporation. Theresidue was triturated with methylene chloride, collected by filtration,washed with ether and dried under vacuum to give4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg,90%).

¹H NMR Spectrum: (DMSOd₆) 4.0(s, 3H); 7.27(s, 1H); 7.43(dd, 1H); 7.56(t,1H); 7.57(s, 1H); 7.72(dd, 1H); 8.5(s, 1H)

MS-ESI: 321 [MH]⁺

A mixture of the trifluoroacetic acid salt of4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g, 7.4mmol), potassium carbonate (6.1 g, 44.2 mmol) and3-(4-methyl-1-piperazinyl)propyl-4-toluene sulphonate (3.0 g, 9.6 mmol)in DMF (60 ml) was stirred at 90° C. for 5 hours and allowed to cool toambient temperature. The reaction mixture was poured into water (700 ml)and extracted 5 times with ethyl acetate. The combined extracts werewashed with water, saturated aqueous sodium hydrogen carbonate, waterand saturated brine. The ethyl acetate solution was dried over magnesiumsulphate, filtered and the solvent removed under vacuum to give aresidue which was purified by silica column chromatography, eluting withdichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevantfractions were combined and evaporated under vacuum to give a residuewhich was triturated with ether, filtered and dried to give4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(1.64 g, 48%).

¹H NMR Spectrum: (DMSOd₆) 1.95 (m, 2H), 2.14 (s, 3H), 2.35 (m, 8H), 2.44(t, 2H), 3.96 (s, 3H), 4.22 (t, 2H), 7.38 (s, 1H), 7.40 (m, 1H), 7.54(m, 2H), 7.68 (m, 1H) and 8.55 (s, 1H)

MS (ESI): 461 (MH)⁺

Elemental analysis Found C 59.6 H 5.7 N 12.2 C₂₃H₂₆ClFN₄O₃ Requires C59.9 H 5.7 N 12.2%

4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(2.6 g, 5.6 mmol) was treated with 2.0 N aqueous hydrochloric acid (45ml) and the mixture stirred at 95° C. for 2 hours. The mixture wascooled, basified by the addition of solid sodium hydrogen carbonate andthe water removed by azeotroping with toluene. The residue was purifiedby silica column chromatography eluting withdichloromethane/methanol/0.880 aqueous ammonia (50/8/1) to give6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazolin-4-one(1.8 g, 96%).

MS (ESI): 333 (MH)⁺

6-Methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazolin-4-one(2.15 g, 6.48 mmol) was suspended in thionyl chloride (25 ml) and DMF(0.18 ml) and stirred under reflux for 2 hours. The thionyl chloride wasevaporated under vacuum and the residue azeotroped twice with toluene.The residue was taken up in water, basified with saturated with aqueoussodium hydrogen carbonate solution and the aqueous solution extracted 4times with dichloromethane. The combined extracts were washed with waterand brine then filtered through phase separating paper. The filtrate wasevaporated under vacuum and the residue purified by silica columnchromatography eluting with dichloromethane/methanol/0.880 aqueousammonia (100/8/1) to give a solid which was triturated with a littleacetone, filtered and dried to give4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (1.2g, 53%). This was used without further purification.

MS (ESI): 351 (MH)⁺

EXAMPLE 177

A mixture of 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline(200 mg, 0.64 mmol), potassium carbonate (102 mg, 0.74 mmol) and7-hydroxyquinoline (107 mg, 0.74 mmol) in DMSO (5 ml) was stirred at100° C. for 5 hours and allowed to cool to ambient temperature. Themixture was poured into water, washed with dichloromethane and extractedtwice with a 10/1 mixture of dichloromethane/methanol. The extracts werewashed with water and brine, dried over magnesium sulphate, filtered andthe filtrate evaporated under vacuum. The residue was purified by silicacolumn chromatography, eluting with dichloromethane/methanol/0.880aqueous ammonia (100/8/1) to give an oil which crystallised ontrituration with ether to give6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline(148 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 3.25 (s, 3H), 3.50 (t, 2H), 3.60 (t, 2H), 3.80(t, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 7.40 (s, 1H), 7.55 (m, 1H), 7.60(m, 1H), 7.65 (s, 1H), 7.90 (d, 1H), 8.10 (d, 1H), 8.40 (m, 1H), 8.50(s, 1H) and 8.90 (m, 1H)

MS (ESI): 422 (MH)⁺

Elemental analysis Found C 65.8 H 5.2 N 10.0 C₂₃H₂₃N₃O₅ Requires C 65.6H 5.5 N 10.0%

The starting material was prepared as follows:

Diethyl azodicarboxylate (864 μl, 5.5 mmol) was added dropwise to amixture of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.2 g, 3.9 mmol) (prepared as described for the starting material inExample 12), triphenylphosphine (1.44 g, 5.5 mmol) and2-(2-methoxyethoxy)ethanol (653 μl, 5.5 mmol) in methylene chloride (70ml) cooled at 0° C. The mixture was stirred for 1.5 hours at ambienttemperature and the solvent was removed by evaporation. The residue waspurified by column chromatography eluting with a mixture of ethylacetate/methylene chloride (50/50 followed by 80/20). The purified solidwas suspended in ether, collected by filtration and dried under vacuumto give6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.70 g, 100%).

¹H NMR Spectrum: (DMSOd₆) 1.13(s, 9H); 3.26(s, 3H); 3.5(m, 2H); 3.65(m,2H); 3.85(m, 2H); 3.91(s, 3H); 4.3(m, 2H); 5.9(s, 2H); 7.2(s, 1H);7.5(s, 1H); 8.4(s, 1H)

Saturated methanolic ammonia (20 ml) was added to a solution of6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(2.26 g, 5.5 mmol) in a mixture of ethanol (40 ml) and methylenechloride (15 ml). The mixture was stirred for 24 hours at ambienttemperature, and further methanolic ammonia (20 ml) was added. Themixture was stirred for a further 24 hours at ambient temperature andthe volatiles were removed by evaporation. The residue was trituratedwith ether, collected by filtration, dried under vacuum to give6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (975mg, 78%).

¹H NMR Spectrum: (DMSOd₆) 3.25(s, 3H); 3.45(t, 2H); 3.6(t, 2H); 3.8(t,2H); 3.9(s, 3H); 4.2(t, 2H); 7.15(s, 1H); 7.45(s, 1H); 8.0(s, 1H)

MS-EI: 294 [M^(•)]⁺

A solution of6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (930mg, 3.16 mmol) in thionyl chloride (15 ml) and DMF (150 μl) was heatedat 60° C. for 1.5 hours. The mixture was allowed to cool and thevolatiles were removed by evaporation and by azeotroping with toluene.The residue was dissolved in methylene chloride and 5% aqueous sodiumhydrogen carbonate solution was added until the aqueous layer was atpH8. The organic layer was separated, washed with brine, dried (MgSO₄)and the solvent removed by evaporation. The residue was purified byflash chromatography eluting with ethyl acetate to give4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (863 mg,87%).

¹H NMR Spectrum: (DMSOd₆) 3.24(s, 3H); 3.47(m, 2H); 3.62(m, 2H); 3.84(t,2H); 4.01(s, 3H); 4.25(t, 2H); 7.41(s, 1H); 7.49(s, 1H); 8.88(s, 1H)

EXAMPLE 178

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168mg, 0.5 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (207 mg, 1.5 mmol),3-methyl-5-hydroxyindole (88 mg, 0.6 mmol), (Can. J. Chem. 1964, 42,514), and DMA (2.0 ml) was purged with nitrogen for 5 minutes at 25° C.This mixture was then stirred at 100° C. for 3 hours then allowed tocool to ambient temperature, was filtered and the filtrate evaporatedunder vacuum. The residue was purified by silica column chromatographyeluting with dichloromethane/methanolic ammonia (7M) (90/10) to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline(155 mg, 69%).

¹H NMR Spectrum: (DMSOd₆) 1.37 (m, 2H), 1.50 (m, 4H), 1.95 (m, 2H), 2.21(s, 3H), 2.34 (m, 4H), 2.42 (t, 2H), 3.96 (s, 3H), 4.22 (t, 2H), 6.95(dd, 1H), 7.16 (s, 1H), 7.35 (m, 3H), 7.58 (s, 1H), 8.48 (s, 1H) and10.82 (s, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis Found C 68.2 H 6.8 N 12.6 C₂₆H₃₀N₄O₃ 0.5 H₂O,Requires C 68.5 H 6.8 N 12.3%

EXAMPLE 179

Using an analogous procedure to that described in Example 178,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline, (preparedas described for the starting material in Example 9), was used to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(154 mg, 79%).

¹H NMR Spectrum: (DMSOd₆) 1.68 (m, 4H), 1.97 (m, 2H), 2.22 (s, 3H), 2.43(m, 4H), 2.55 (t, 2H), 3.96 (s, 3H), 4.22 (t, 2H), 6.93 (dd, 1H), 7.16(s, 1H), 7.35 (m, 3H), 7.58 (s, 1H), 8.48 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 433 (MH)⁺

m.p. 75–77° C.

EXAMPLE 180

Using an analogous procedure to that described in Example 178,4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline was used to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline(156 mg, 80%).

¹H NMR Spectrum: (DMSOd₆) 1.38 (m, 2H), 1.50 (m, 4H), 2.24 (s, 3H), 2.73(t, 2H), 3.96 (s, 3H), 4.28 (t, 2H), 6.93 (dd, 1H), 7.16 (s, 1H), 7.32(d, 1H), 7.37 (m, 2H), 7.58 (s, 1H), 8.47 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 433 (MH)⁺

Elemental analysis Found C 67.0 H 6.5 N 13.0 C₂₅H₂₈N₄O₃ 0.75 H₂ORequires C 67.3 H 6.6 N 12.6%

The starting material was prepared as follows:

1-(2-Chloroethyl)piperidine hydrochloride (0.83 g, 4.5 mmol) was addedto 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.73 mmol),(prepared as described for the starting material in Example 1), andpotassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml), and the mixtureheated at 110° C. for 2.5 hours and allowed to cool. The insolubles wereremoved by filtration, and the volatiles were removed from the filtrateby evaporation. The residue was purified by column chromatographyeluting with methylene chloride/methanol (9/1) to give6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.2 g, 85%).

¹H NMR Spectrum: (DMSOd₆) 1.38(m, 2H); 1.50(m, 4H); 2.4–2.5(m, 4H);2.75(t, 2H); 3.95(s, 3H); 4.27(t, 2H); 7.30(m, 3H); 7.40(s, 1H); 7.46(m,2H); 7.54(s, 1H); 8.52(s, 1H)

MS-ESI: 380 [MH]⁺

A mixture of 6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline 1.15g, 3.0 mmol) and 2M hydrochloric acid (20 ml) was heated at 90° C. for 2hours and allowed to cool. The mixture was neutralised with solid sodiumhydrogen carbonate and extracted with methylene chloride. The organicphase was separated, passed through phase separating paper and thevolatiles removed by evaporation to give a solid product (230 mg). Theaqueous phase was adjusted to pH10, the resulting precipitate wascollected by filtration, washed with water and dried to give a secondcrop of product (220 mg). The products were combined to give6-methoxy-7-(2-piperidinoethoxy)-3,4-dihydroquinazolin-4-one (450 mg,50%).

MS-ESI: 304 [MH]⁺

A mixture of6-methoxy-7-(2-piperidinoethoxy)-3,4-dihydroquinazolin-4-one (440 mg,1.45 mmol), thionyl chloride (15 ml) and DMF (3 drops) was heated atreflux for 3 hours then allowed to cool. The excess thionyl chloride wasremoved by evaporation and the residue was azeotroped with toluene togive a crude 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazolinehydrochloride (640 mg).

4-Chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline hydrochloride wassuspended in methylene chloride (10 ml) and saturated aqueous sodiumhydrogen carbonate solution (5 ml) then stirred vigorously for 10minutes at ambient temperature. The layers were separated and theorganic layer dried (MgSO₄) then evaporated to give a white solid. Thissolid was triturated with methanol (2.5 ml), the resulting solidfiltered off, washed with cold methanol and dried to give4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (0.36 g).

EXAMPLE 181

Using an analogous procedure to that described in Example 178,4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline,(prepared as described for the starting material in Example 152), wasused to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline(104 mg, 49%).

¹H NMR Spectrum: (DMSOd₆) 2.08 (m, 2H), 2.22 (s, 3H), 2.80 (s, 3H), 2.88(s, 3H), 3.27 (t, 2H), 3.97 (s, 3H), 4.22 (t, 2H), 6.95 (dd, 1H), 7.17(s, 1H,), 7.35 (m, 3H), 7.59 (s, 1H), 8.48 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 471 (MH)⁺

Elemental analysis Found C 57.0 H 5.6 N 11.4 C₂₃H₂₆F₄N₄O₅S 0.5 H₂O,Requires C 57.5 H 5.7 N 11.7%

EXAMPLE 182

A mixture of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218 mg,0.68 mmol), (prepared as described for the starting material in Example9), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol) andpotassium carbonate (280 mg, 2.0 mmol) in DMF (4 ml) was stirred at 95°C. for 6 hours and allowed to cool to ambient temperature. The reactionmixture was treated with 1.0 N aqueous sodium hydroxide solution andallowed to stir at ambient temperature for a few minutes. The resultingprecipitate was filtered off, washed with water and air dried to give acrude product which was purified by column chromatography, eluting withdichloromethane/methanol/880 ammonia (100/8/1). The relevant fractionswere combined and evaporated ‘in vacuo’ to give a white solid. This wasrecolumned using dichloromethane/methanol (4/1) solvent to give a whitesolid which was triturated with acetone, filtered and dried to give6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline(50 mg, 18%).

m.p. 184.0–185.5° C.

¹H NMR Spectrum: (DMSOd₆) 1.70 (m, 4H), 1.99 (m, 2H), 2.46 (m, 4H), 2.58(t, 2H), 4.00 (s, 3H), 4.26 (t, 2H), 6.48 (t, 1H), 7.36 (s, 1H), 7.55(t, 1H), 7.60 (s, 1H), 7.92 (d, 1H), 8.19 (d, 1H), 8.50 (s, 1H) and11.78 (br s, 1H)

MS (ESI): 420 (MH)⁺

Elemental analysis Found C 63.9 H 5.9 N 16.1 C₂₃H₂₅N₅O₃ 0.7 H₂O RequiresC 63.9 H 6.2 N 16.2%

The starting material was prepared as follows:—

A suspension of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (210 mg, 1.42 mmol),(Heterocycles 50, (2), 1065–1080, (1999)), in dichloromethane (10 ml)was stirred in an inert atmosphere, a 1.0M solution of boron tribromidein dichloromethane (4.3 ml, 4.3 mmol) added dropwise and the mixturestirred at ambient temperature overnight. The reaction mixture was takento pH6 by the dropwise addition of 5N aqueous sodium hydroxide andfurther diluted with water. The aqueous solution was extracted severaltimes with ethyl acetate, the extracts combined, washed with waterfollowed by brine and dried over magnesium sulphate. The ethyl acetatesolvent was removed ‘in vacuo’ and the residue purified by columnchromatography, eluting with dichloromethane/methanol (95/5), to give awhite solid. The solid was triturated with ether, filtered and dried togive 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (108 mg, 57%).

m.p. 206–209° C.

¹H NMR Spectrum: (DMSOd₆) 6.25 (s,1H), 7.27 (s,1H), 7.33 (s, 1H), 7.82(s, 1H), 9.00 (s,1H) and 11.20 (s, 1H)

MS (ESI): 135 (MH)⁺

EXAMPLE 183

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168mg, 0.5 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (345 mg, 5.0 mmol),5-hydroxy-2-indolecarboxylic acid (106 mg, 0.6 mmol) and DMA (2.0 ml)was purged with nitrogen for 5 minutes at 25° C. This mixture was thenstirred at 100° C. for 3 hours, allowed to cool to ambient temperature,filtered and the filtrate evaporated under vacuum. The residue waspurified on octadecylsilane reverse phase silica eluting withacetonitrile/water/trifluoroacetic acid (as a gradient from 30/69.8/0.2to 50/49.8/0.2) and the product further purified by silica columnchromatography eluting with dichloromethane/methanolic ammonia (7M)(90/10) to give4-(2-carboxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(85 mg 36%).

¹H NMR Spectrum: (DMSOd₆) 1.43 (m, 2H), 1.56 (m, 4H), 2.04 (m, 2H), 2.59(m, 6H), 3.97 (s, 3H), 4.24 (t, 2H), 7.01 (s, 1H), 7.11 (dd, 1H), 7.36(s, 1H), 7.48 (m, 2H), 7.58 (s, 1H), 8.48 (s, 1H) and 11.53 (br s, 1H)

MS (ESI): 477 (MH)⁺

EXAMPLE 184

4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (0.15 g, 0.45mmol), (prepared as described for the starting material in Example 50),potassium carbonate (94 mg, 0.68 mmol) and 7-hydroxyquinoline (79 mg,0.54 mmol) were suspended in anhydrous DMF (1.5 ml) and heated to 90° C.overnight. The compound was precipitated upon addition of water. Theprecipitate was collected by filtration, washed with water and driedunder vacuum over phosphorus pentoxide to give6-methoxy-7-(3-methylsulphonylpropoxy)4-(quinolin-7-yloxy)quinazoline(161 mg, 81%).

¹H NMR Spectrum: (DMSOd₆) 2.26 (m, 2H); 3.08 (s, 3H); 3.35 (m, 2H); 4.03(s, 3H); 4.38 (m, 2H); 7.45 (s, 1H); 7.60 (m, 1H); 7.65 (m, 1H); 7.70(s, 1H); 7.95 (d, 1H); 8.15 (d, 1H); 8.46 (d, 1H); 8.60 (s, 1H); 8.95(d, 1H)

MS (ESI): 440 [MH]⁺

EXAMPLES 185–188

Using an analogous procedure to that described in Example 184,4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (0.15 g, 0.45mmol), (prepared as described for the starting material in Example 50),was reacted with the appropriate phenols to give the compounds in TableX.

TABLE X

Example number weight (mg) yield % MS-ESI [MH]+ AR note 185 199 93 474

a 186 171 85 422

b 187 183 88 460

c 188  83 40 455

d a Using 4-chloro-7-hydroxyquinoline (96 mg) gave4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.24(m, 2H); 3.04(s, 3H); 3.35(m, 2H); 3.99(s,3H); 4.32(m, 2H); 7.42(s, 1H); 7.64(s, 1H); 7.80(d, 2H); 8.04(d, 1H);8.29(d, 1H); 8.55(s, 1H); 8.87(d, 1H) b Using 5-hydroxy-2-methylindole(80 mg) gave6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.24(m, 2H); 2.40(s, 3H); 3.05(s, 3H); 3.35(m,2H); 4.0(s, 3H); 4.32(m, 2H); 6.13(s, 1H); 6.88(d, 1H); 7.25(d, 1H);7.32(d, 1H); 7.39(s, 1H); 7.60(s, 1H); 8.50(s, 1H) c Using5-hydroxy-2-methylbenzothiazole (90 mg) gave6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.24(m, 2H); 2.28(s, 3H); 3.05(s, 3H); 3.35(m,2H); 4.0(s, 3H); 4.32(m, 2H); 7.36(d, 1H); 7.41(s, 1H); 7.65(s, 1H);7.87(d, 1H); 8.11(d, 1H); 8.53(s, 1H) d Using 2,7-dihydroxynaphtalene(87 mg) gave4-(7-hydroxy-2-naphthyloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.24(m, 2H); 3.05(s, 3H); 3.35(m, 2H); 3.98(s,3H); 4.32(m, 2H); 7.06(d, 1H); 7.12(s, 1H); 7.18(d, 1H); 7.40(d, 1H);7.59(m, 2H); 7.85(m, 2H); 8.55(d, 1H); 9.8(br s, 1H)

EXAMPLE 189

To a portion of 2-chloro-5-hydroxybenzimidazole (191 mg, 0.75 mmol) inDMF (3 ml) was added sodium hydride (60 mg, 1.5 mmol) under argon atambient temperature. Ten minutes later4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline (200 mg,0.62 mmol), (prepared as described for the starting material in Example10), was added and the mixture heated at 100° C. for 2 hours. More2-chloro-5-hydroxybenzimidazole (30 mg, 0.12 mmol) and sodium hydride(11 mg, 0.28 mmol) were then added as the reaction was found to beincomplete. The heating was continued for an additional 1 hour. Work-upusing ethyl acetate and a saturated aqueous solution of ammoniumchloride followed by drying of the organic phase (MgSO₄) and evaporationof the solvent gave a crude product which was adsorbed on alumina usingdichloromethane/methanol and purified by flash chromatography usingneutral alumina and dichloromethane/methanol (98:2) as the eluent.Evaporation of the solvent and trituration in ether gave4-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(46 mg, 16%).

¹H NMR Spectrum: (DMSOd₆+TFA) 1.60 (m, 2H); 2.05 (d, 2H); 2.15 (m, 1H);2.80 (s, 3H); 3.05 (m, 2H); 3.55 (m, 2H); 4.05 (s, 3H); 4.15 (d, 2H);7.20 (dd, 1H); 7.50 (dd, 2H); 7.65 (d, 1H); 7.70 (s, 1H); 8.80 (s, 1H)

MS (ESI): 454 [MH]⁺

The starting material was synthesised as follows:

2-Chloro-5-methoxybenzimidazole (0.3 g, 1.64 mmol) was suspended indichloromethane (20 ml) under argon followed by the addition of borontribromide (233 ul, 2.46 mmol). The reaction mixture was stirred for 2hours at ambient temperature. The solvent was evaporated and theresulting powder was added in portions to methanol (30 ml). Silica wasadded and the solvent was evaporated. The resulting powder was placed onthe top of a silica column and the product was eluted off usingdichloromethane/methanol (95/5). Evaporation of the solvent andtrituration in ether gave 2-chloro-5-hydroxybenzimidazole (440 mg, 99%).

EXAMPLE 190

Using an analogous procedure to that described in Example 189,4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline,(prepared as described for the starting material in Example 10); wasreacted with 5-hydroxy-2-methylbenzimidazole (200 mg, 0.62 mmol) andafter work-up and purification on a 10 g silica ISOLUTE column usingsuccessively dichloromethane, dichloromethane/methanol (95/5) anddichloromethane/methanol saturated with ammonia (95/5), gave6-methoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(68 mg, 25%).

¹H NMR Spectrum: (DMSOd₆+TFA) 1.60 (m, 2H); 2.10 (m, 2H); 2.20 (m, 1H);2.80 (s, 3H); 2.85 (s, 3H); 3.05 (m, 2H); 3.50 (m, 2H); 4.05 (s, 3H);4.15 (d, 2H); 7.50 (s, 1H); 7.55 (d, 1H); 7.70 (s, 1H); 7.85 (d, 1H);7.90 (d, 1H); 8.65 (s, 1H)

MS (ESI): 434 [MH]⁺

The starting material was prepared as follows:

The free base of 4-methoxy-1,2-phenylenediamine dihydrochloride (10 g)was obtained by shaking it with a mixture of ethyl acetate and asaturated aqueous solution of sodium hydrogen carbonate. The organicphase was then washed with brine, dried (MgSO₄) and the solventevaporated. The obtained dark oil (6.08 g, 50 mmol) was solubilised intoluene (60 ml) and p-toluene sulfonic acid (60 mg) and triethylorthoacetate (9.15 ml, 50 mmol) were added in turn. The mixture washeated to 110° C. until no more ethanol distilled off. The remainingtoluene was removed by rotary evaporation and the residue purified byflash chromatography using dichloromethane/methanol (95/5) as theeluent. The obtained dark oil was triturated in ether and the solidcollected by filtration to give 5-methoxy-2-methylbenzimidazole (4.15 g,51%).

¹H NMR Spectrum (DMSOd₆+TFA) 2.75 (s, 3H); 3.85 (s, 3H); 7.15 (dd, 1H);7.25 (s, 1H); 7.70 (d, 1H)

Using an analogous procedure to that described for the synthesis of2-chloro-5-hydroxybenzimidazole in Example 189,5-methoxy-2-methylbenzimidazole (4.0 g, 25 mmol) was reacted with borontribromide (7 ml, 74 mmol) in dichloromethane (150 ml) to give, afterwork-up and purification by flash chromatography usingdichloromethane/methanol (90/10), 5-hydroxy-2-methylbenzimidazole (4.4g, 76%).

¹H NMR Spectrum (DMSOd₆) 2.70 (s, 3H); 6.95 (dd, 1H); 7.00 (d, 1H); 7.55(d, 1H)

EXAMPLE 191

4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (200mg, 0.62 mmol), (prepared as described for the starting material inExample 10), was suspended in DMF (3 ml) under argon.3-Cyano-7-hydroxyquinoline (116 mg, 0.68 mmol) and potassium carbonate(129 mg, 0.93 mmol) were added and the reaction mixture was heated at95° C. for 90 minutes. Upon cooling to ambient temperature the mixturewas diluted with dichloromethane and poured on the top of an ISOLUTEsilica column. Elution was done using successively dichloromethane,dichloromethane/methanol (95/5) and dichloromethane/methanol saturatedwith ammonia (95/5). Evaporation of the solvent and trituration of thesolid in ether gave4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(244 mg, 86%).

¹H NMR Spectrum: (DMSOd₆+TFA) 1.60 (m, 2H); 2.10 (m, 3H); 2.85 (s, 3H);3.05 (m, 2H); 3.55 (m, 2H); 4.05 (s, 3H); 4.20 (d, 2H); 7.55 (s, 1H);7.80 (s, 1H); 7.85 (dd, 1H); 8.15 (s, 1H); 8.3 (d, 1H); 8.85 (s, 1H);9.20 (s, 1H); 9.25 (s, 1H)

MS (ESI): 456 [MH]⁺456

The starting material was prepared as follows:

-   -   m-Anisidine (50 g, 407 mmol) and diethyl ethoxymethylenemalonate        (102 g, 407 mmol) were heated at 60° C. for 20 minutes. Diphenyl        ether (270 ml) was then added and the temperature was raised to        240° C. over 30 minutes. The ethanol formed distilled off.        Heating was maintained at this temperature for 1 hour then the        reaction mixture was allowed to cool to 120° C. at which point        the reaction mixture was diluted with heptane and allowed to        stand overnight at ambient temperature. The brown solid was        collected by filtration and washed with methanol and ether to        give ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate        (45 g, 45%). This reaction was repeated twice.

¹H NMR Spectrum: (DMSOd₆) 1.25 (t, 3H); 3.85 (s, 3H); 4.20 (q, 2H); 6.95(d, 1H); 7.00 (s, 1H); 8.05 (d, 1H); 8.50 (s, 1H)

Phosphorus oxychloride (88 ml) was added to ethyl7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (58 g, 235 mmol) andthe mixture was heated at reflux for 45 minutes under anhydrousconditions. Upon cooling to ambient temperature, phosphorus oxychloridewas evaporated and the solid residue was added in portions to a mixtureof ammonia (150 ml) and ice (200 g). External cooling as well as furtheraddition of ammonia to maintain the pH around 8 was needed during thishydrolysis step. The aqueous phase was extracted with dichloromethaneand the organic phase was washed with water and brine, dried (MgSO₄) andconcentrated to about 300 ml. Pentane (400 ml) was added and theprecipitate formed collected by filtration. Drying under vacuum gave4-chloro-3-ethoxycarbonyl-7-methoxyquinoline (45.5 g, 73%).

¹H NMR Spectrum: (DMSOd₆) 1.40 (t, 3H); 4.00 (s, 3H); 4.45 (q, 2H); 7.45(dd, 1H); 7.55 (d, 1H); 8.30 (d, 1H); 9.10 (s, 1H)

4-Chloro-3-ethoxycarbonyl-7-methoxyquinoline (43 g, 162 mmol) wasdissolved in acetic acid (250 ml), with 10% palladium on charcoal (1.5g) and hydrogenated at atmospheric pressure during 8 hours. The catalystwas removed by filtration over a pad of celite and the solventevaporated. The residue was diluted with water and the pH adjusted to7–8 with a saturated solution of sodium hydrogen carbonate. The solidwas collected by filtration, washed with water and dried under vacuumover phosphorus pentoxide to give 3-ethoxycarbonyl-7-methoxyquinoline(33 g, 88%) as a beige powder.

¹H NMR Spectrum: (DMSOd₆) 1.40 (t, 3H); 3.95 (s, 3H); 4.40 (q, 2H); 7.35(dd, 1H); 7.50 (d, 1H); 8.15 (d, 1H); 8.90 (d, 1H); 9.25 (d, 1H)

3-Ethoxycarbonyl-7-methoxyquinoline (28 g, 120 mmol) was added to amethanol solution saturated with ammonia. The suspension was stirred atambient temperature in a glass pressure vessel for 2 weeks. The whitesolid was collected by filtration, washed with methanol and dried undervacuum to give 3-carbamoyl-7-methoxyquinoline (21 g, 86%).

¹H NMR Spectrum (DMSOd₆) 3.95 (s, 3H); 7.35 (dd, 1H); 7.45 (d, 1H); 7.60(br s, 1H); 8.00 (d, 1H); 8.20 (br s, 1H); 8.75 (s, 1H); 9.25 (s, 1H)

3-Carbamoyl-7-methoxyquinoline (4 g, 20 mmol) was suspended in anhydrousdichloromethane (60 ml) under argon. Anhydrous dimethyl sulphoxide (2.25ml, 32 mmol) was added, the mixture was cooled to −78° C. and a solutionof oxalyl chloride (2.08 ml, 24 mmol) in dichloromethane (20 ml) wasadded dropwise over the course of 1 hour. 15 Minutes after the end ofthe addition, triethylamine (8.3 ml, 60 mmol) was added dropwise and theheterogeneous reaction mixture stirred for an additional 1 hour at −78°C. then left to rise to ambient temperature. The unreacted startingmaterial was removed by filtration and the filtrate was diluted withwater and extracted with ethyl acetate. The organic phases werecombined, washed with brine, dried (MgSO₄) and the solvent evaporated.The residue was purified by flash chromatography usingdichloromethane/methanol (97/3). The obtained solid was triturated withether and gave, after drying under vacuum, 3-cyano-7-methoxyquinoline(1.47 g, 40%).

¹H NMR Spectrum (DMSOd₆) 4.00 (t, 3H); 7.40 (dd, 1H); 7.50 (d, 1H); 8.00(d, 1H); 8.95 (s, 1H); 9.10(d, 1H)

3-Cyano-7-methoxyquinoline (380 mg, 2.1 mmol) was suspended in benzene(10 ml), aluminium trichloride (826 mg, 6.2 mmol) was added and themixture heated at reflux for 30 minutes. More aluminium trichloride (275mg, 2.1 mmol) was added and the mixture refluxed for a further 2 hours.The solvent was evaporated, the dark green solid was added to ice andextracted with ethyl acetate. The organic phase was washed with brine,dried (MgSO₄) and evaporated. The solid was found to contain somealuminium salts which were removed as follows. The solid was dissolvedin dichloromethane (200 ml) was stirred vigorously with a saturatedsodium hydrogen carbonate solution for 1 hour. The product was collectedby filtration of the aqueous phase and dried over phosphorus pentoxideunder vacuum to give 3-cyano-7-hydroxyquinoline (238 mg, 68%).

¹H NMR Spectrum (DMSOd₆) 7.25 (d, 1H); 7.30(d, 1H); 7.95 (d, 1H); 8.85(d, 1H); 9.00 (d, 1H)

EXAMPLE 192

To6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)quinazoline(110 mg, 0.2 mmol) in solution in dichloromethane (3 ml) was added TFA(0.3 ml) and the mixture stirred for 1 hour at ambient temperature. Thesolvents were evaporated and the remaining oil was diluted withdichloromethane and the pH adjusted to 9 with a saturated solution ofsodium hydrogen carbonate. The organic phase was washed with, brine,dried (MgSO₄), filtered and the solvent evaporated to give6-methoxy-7-(3-morpholinopropoxy)4-(1,2,3,4-tetrahydroquinolin-6-yloxy)quinazoline(84 mg, 93%).

¹H NMR Spectrum: (CDCl₃) 1.95 (m, 2H); 2.15 (m, 2H); 2.45 (m, 4H); 2.60(t, 2H); 2.80 (t, 2H); 3.35 (t, 2H); 3.75 (m, 4H); 3.90 (br s, 1H); 4.05(s, 3H); 4.30 (t, 2H); 6.55 (d, 1H); 6.85 (m, 2H); 7.30 (s, 1H); 7.55(s, 1H); 8.65 (s, 1H)

MS (ESI): 451 [MH]⁺

Elemental analysis: Found C 66.4 H 6.9 N 12.4 C₂₅H₃₀N₄O₄ Requires C 66.7H 6.7 N 12.4%

The starting material was prepared as follows:

6-Hydroxyquinoline (1 g, 6.9 mmol) was dissolved in methanol andhydrogenated at 3 atmospheres pressure with platinum(IV) oxide (276 mg)over 24 hours. The catalyst was removed by filtration over a pad ofcelite and the solvent was evaporated. The solid was washed with etherto give 6-hydroxy-(1,2,3,4)-tetrahydroquinoline (698 mg, 68%).

¹H NMR Spectrum (DMSOd₆) 1.75 (m, 2H); 2.60 (m, 2H); 3.05 (m, 2H); 4.90(br s, 1H); 6.30 (m, 3H); 8.25 (br s, 1H)

6-Hydroxy-(1,2,3,4)-tetrahydroquinoline (250 mg, 1.7 mmol) was suspendedin acetone (1 ml) and trichloromethane (1 ml) under argon.Tert-Butoxycarbonylanhydride (365 mg, 1.7 mmol) in solution in acetonewas added dropwise followed by THF (2 ml) to help the solubilisation.The reaction mixture was stirred overnight at ambient temperature, thesolvent was evaporated, the residue was partitioned between ethylacetate and water, the organic phase was washed with water, brine, dried(MgSO₄), filtered and the solvent evaporated. The resulting gum waspurified by flash chromatography using dichloromethane/methanol (97/3)as solvent. Evaporation of the solvent gave6-hydroxy-4-(1-tertbutoxycarbonyl-1,2,3,4tetrahydroquinoline (344 mg,82%) as a brown foam.

¹H NMR Spectrum: (DMSOd₆) 1.50 (m, 9H); 1.90 (m, 2H); 2.70 (t, 2H); 3.65(t, 2H); 4.75 (br s, 1H); 6.55 (d, 1H); 6.65 (dd, 1H); 7.45 (d, 1H) b

6-Hydroxy-4-(1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinoline (82 mg,0.32 mmol) was dissolved in anhydrous dimethylformamide under argon,with potassium carbonate (61 mg, 0.44 mmol) and4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (100 mg, 0.3mmmol), (prepared as described for the starting material in Example 1).No reaction occurred after 2 hours at 60° C. Sodium hydride (12 mg, 0.3mmol) was added and the reaction mixture was heated at 120° C. for 90minutes. The cooled mixture was poured into water and ethyl acetate. Theorganic phase was washed with water, brine, dried (MgSO₄), filtered andthe solvent evaporated. The residue was purified by flash chromatographyusing first dichloromethane/methanol (97/3) as solvent. Evaporation ofthe solvent gave6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)quinazoline(115 mg, 71%) as a white solid.

¹H NMR Spectrum: (DMSOd₆) 1.55 (s, 9H); 1.95 (m, 2H); 2.15 (m, 2H); 2.50(m, 4H); 2.60 (t, 2H); 2.85 (t, 2H); 3.75 (m, 6H); 4.05 (s, 3H); 4.30(t, 2H); 7.00 (m, 2H); 7.35 (s, 1H); 7.55 (s, 1H); 7.80 (d, 1H); 8.65(s, 1H)

EXAMPLE 193

Using an analogous procedure to that described in Example 192,4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(169 mg, 0.32 mmol) was reacted with TFA (1 ml) to give, after work-upand purification,4-(2,3-dihydro-1H-indol-5-yl)oxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(124 mg, 91%).

¹H NMR Spectrum: (CDCl₃) 1.90 (br, 4H); 2.30 (br, 2H); 2.70 (br d, 6H);3.10 (t, 2H); 3.65 (t, 2H); 4.05 (s, 3H); 4.30 (t, 2H); 6.70 (d, 1H);6.80 (dd, 1H); 7.00 (s, 1H); 7.30 (s, 1H); 7.55 (s, 1H); 8.65 (s, 1H)

MS (ESI): 421 [MH]⁺

The starting material was prepared as follows:

5-Hydroxyindole (2 g, 15 mmol) was dissolved in methanol (60 ml) underargon. Sodium cyanoborohydride (1.89 g, 30 mmol) and trifluoroboronetherate (4.2 ml, 33 mmol) were added and the mixture was heated atreflux for 3 hours then left to cool to ambient temperature. The solventwas evaporated and the residue was partitioned between ethyl acetate andwater. Ammonia was added to adjust the pH to 10 and the aqueous phasewas extracted with more ethyl acetate. The combined organic phases werewashed with water, brine, dried (MgSO₄), filtered and the solventevaporated. The residue was purified by flash chromatography usingdichloromethane/methanol (95/5) as solvent. Evaporation of the solventgave 5-hydroxy-2,3-dihydro-1H-indole (1.45 g, 73%) as an off whitesolid.

¹H NMR Spectrum: (DMSOd₆+ TFA) 3.15 (t, 2H); 3.70 (t, 2H); 6.75 (dd,1H); 6.85 (d, 1H); 7.30 (d, 1H)

5-Hydroxy-2,3-dihydro-1H-indole (1.5 g, 11.1 mmol) was suspended in amixture of acetone (7 ml) trichloromethane (7 ml) and THF (6 ml).tert-Butoxycarbonylanhydride (2.42 g, 11 mmol) in solution in THF (7 ml)was added dropwise. The reaction mixture was stirred overnight atambient temperature, the solvent was evaporated, the residue waspartitioned between ethyl acetate and water, the organic phase waswashed with water, brine, dried (MgSO₄), filtered and the solventevaporated. The solid was purified by flash chromatography usingdichloromethane/methanol (95/5) as solvent. Evaporation of the solventgave 5-hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole (2.28 g, 87%) asan off white solid.

¹H NMR Spectrum: (CDCl₃) 3.05 (t, 2H); 3.95 (br s, 2H); 4.70 (br s, 1H);6.60 (d, 1H); 6.65 (s, 1H); 7.70 (br s, 1H)

Sodium hydride (22 mg, 0.56 mmol) was suspended in anhydrousdimethylformamide under argon.5-Hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole (131 mg, 0.56 mmol)was added followed 10 minutes later by4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (150 mg,0.47 mmol), (prepared as described for the starting material in Example9). The reaction mixture was heated at 110° C. for 3 hours, cooled toambient temperature and partitioned between ethyl acetate and water. Theorganic phase was washed with water, brine, dried (MgSO₄), filtered andthe solvent evaporated. The residue was purified by flash chromatographyusing increasingly polar solvent mixtures starting withdichloromethane/methanol (90/10) and ending withdichloromethane/methanol/methanol saturated with ammonia (80/15/5).Evaporation of the solvent gave4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(178 mg, 73%) as a white solid.

¹H NMR Spectrum: (DMSOd₆) 1.60 (s, 9H); 1.80 (m, 4H); 2.20 (m, 2H); 2.55(m, 4H); 2.70 (t, 2H); 3.15 (t, 2H); 4.05 (br s, 5H); 4.30 (t, 2H); 7.00(d, 1H); 7.05 (s, 1H); 7.30 (s, 1H); 7.55 (s, 1H); 7.90 (br s, 1H); 8.60(s, 1H)

EXAMPLE 194

Using an analogous procedure to that described in Example 192,4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(191 mg, 0.37 mmol) was reacted with TFA (1 ml) to give, after work-upand purification,4-(2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(103 mg, 67%).

¹H NMR Spectrum: (CDCl₃) 1.65 (m, 2H); 2.00 (m, 3H); 2.25 (m, 2H); 2.45(s, 3H); 3.10 (m, 4H); 3.65 (t, 2H); 4.05 (s, 3H); 4.10 (d, 2H); 6.70(d, 1H); 6.85 (dd, 1H); 7.0 (s, 1H); 7.25 (s, 1H); 7.55 (s, 1H); 8.60(s, 1H)

MS (ESI): 421 [MH]⁺

The starting material was prepared as follows:

Using an analogous procedure to that described in Example 193,4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (150 mg,0.47 mmol), (prepared as described for the starting material in Example10), was reacted with 5-hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole(132 mg, 0.56 mmol), (prepared as described for the starting material inExample 193), to give, after work-up and purification,4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(197 mg, 81%) as a white solid.

¹H NMR Spectrum: (CDCl₃) 1.50 (br s, 1H); 2.00 (m, 5H); 2.30 (s, 3H);2.90 (d, 2H); 3.15 (t, 2H); 4.05 (br s, 7H); 7.05 (br s, 2H); 7.30 (s,1H); 7.55 (s, 1H); 7.95 (br s, 1H); 8.60 (s, 1H)

EXAMPLE 195

To a suspension of 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline(250 mg, 0.78 mmol), (prepared as described for the starting material inExample 180), in DMF (10 ml) was added anhydrous potassium carbonate(320 mg, 2.30 mmol) and 7-hydroxyquinoline (135 mg, 0.94 mmol), and thereaction heated under reflux at 90C for 1 hour. The reaction was cooledto ambient temperature and 1N aqueous sodium hydroxide added. Theresulting precipitate was filtered, washed with water and acetone, anddried under suction to give6-methoxy-7-(2-piperidinoethoxy)-4-(quinolin-7-yloxy)quinazoline (248mg, 0.58 mmol, 75%) as a white solid.

¹H NMR Spectrum: d_(H) (300 MHz, CDCl₃): 1.5 (2H, m; NCH₂CH₂CH₂), 1.6(4H, m; 2×NCH₂CH₂), 2.6 (4H, t; 2×NCH₂); 2.9 (2H, t; NCH₂), 4.1 (3H, s;OCH₃), 4.3 (2H, t; OCH₂), 7.3 (1H, s; ArH), 7.4 (1H, dd; ArH), 7.5 (1H,dd; ArH), 7.6 (1H, s; ArH), 7.9 (1H, d; ArH), 8.0 (1H, d; ArH), 8.2 (1H,d; ArH), 8.6 (1H, s; ArH) and 8.9 (1H, dd; ArH)

m/z (ESP+) 431 (MH⁺, 100%)

EXAMPLE 196

To a suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.82 g,6.1 mmol), (prepared as described for the starting material in Example1), in DMF (50 ml) was added potassium carbonate (2.50 g, 18.1 mmol) and7-hydroxyquinoline (1.06 g, 7.3 mmol), and the reaction heated underreflux at 90C for 4 hours. The reaction was poured into 1N aqueoussodium hydroxide and the resulting precipitate filtered, washed withwater, and dried under suction. Further drying in a vacuum oven gave7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (1.50 g, 3.7 mmol,60%) as a cream solid.

¹H NMR Spectrum: d_(H) (300 MHz, DMSO-d₆): 4.0 (3H, s; OCH₃), 5.4 (2H,s; OCH₂), 7.3–7.7 (9H, m; 9×ArH), 7.9 (1H, br s; ArH), 8.1 (1H, d; ArH),8.4 (1H, d; ArH), 8.5 (1H, s; ArH) and 8.9 (1H, d; ArH)

EXAMPLE 197

A solution of 7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline(1.50 g, 3.70 mmol), (prepared as described in Example 196), intrifluoroacetic acid (50 ml) was heated at reflux for 150 minutes. Thereaction was concentrated in vacuo and the reaction neutralised withsaturated aqueous ammonium hydroxide. The resulting precipitate wasfiltered, washed with acetone and dried under suction to give7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (0.90 g, 2.82 mmol,76%) as a white solid.

¹H NMR Spectrum: d_(H) (300 MHz, DMSO-d₆): 4.0 (3H, s; OCH₃), 7.1 (1H,s; ArH), 7.3–7.4 (3H, m; 3×ArH), 7.9 (1H, br s; ArH), 8.1 (1H, d; ArH),8.4–8.5 (2H, d; 2×ArH) and 8.9 (1H, d; ArH)

m/z (ESP+) 320 (MH⁺, 100%)

EXAMPLE 198

To a suspension of 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline(450 mg, 1.40 mmol), (prepared as described in Example 197), in DMF (50ml) was added anhydrous potassium carbonate (773 mg, 5.60 mmol) and4-(2-hydroxyethyl)morpholine (335 mg, 1.80 mmol), and the reactionheated under reflux for 2 hours. The DMF was evaporated in vacuo, andthe residue partitioned between dichloromethane and 1N aqueous sodiumhydroxide. The mixture was extracted with dichloromethane (3×200 ml),dried (MgSO₄) and concentrated in vacuo. The crude product wastriturated with hexane/ether to afford a solid which was filtered anddried under suction to give6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline (430mg, 1.00 mmol, 71%) as a light brown solid.

¹H NMR Spectrum: d_(H) (300 MHz, CDCl₃): 2.7 (4H, t; 2×NCH₂); 3.0 (2H,t; NCH₂), 3.7 (4H, t; 2×OCH₂), 4.1 (3H, s; OCH₃), 4.4 (2H, t; OCH₂), 7.2(1H, s; ArH), 7.4 (1H, dd; ArH), 7.5 (1H, dd; ArH), 7.6 (1H, s; ArH),7.9 (1H, d; ArH), 8.0 (1H, br s; ArH), 8.2 (1H, d; ArH), 8.6 (1H, s;ArH) and 8.9 (1H, dd; ArH)

m/z (ESP+) 433 (MH⁺, 100%)

Elemental analysis Found C 65.0 H 5.6 N 12.6 C₂₄H₂₄N₄O₄ 0.5H₂O RequiresC 65.3 H 5.7 N 12.7%

EXAMPLE 199

To a solution of 7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline(100 mg, 0.31 mmol), (prepared as described in Example 197), and(S)-(+)-5-(hydroxymethyl)-2-pyrrolidinone (101 mg, 0.47 mmol) indichloromethane (10 ml) was added triphenylphosphine (244 mg, 0.93 mmol)and DEAD (0.15 ml, 162 mg, 0.93 mmol), and the reaction stirred atambient temperature overnight. The reaction mixture was placed directlyonto a 2 g SCX ion-exchange column, and eluted with dichloromethane,then dichloromethane/methanol (4/1), thendichloromethane/methanol/ammonium hydroxide (20/5/1). The appropriatefractions were concentrated in vacuo, and the residue triturated withether to give a solid which was filtered and dried under suction to give(5S)-6-methoxy-7-(5-oxo-pyrrolidin-2-ylmethoxy)-4-(quinolin-7-yloxy)quinazoline(55 mg, 0.13 mmol, 43%) as a yellow solid.

¹H NMR Spectrum: d_(H) (300 MHz, CDCl₃): 2.3–2.5 (4H, m;2×pyrrolidinone-CH₂), 4.0–4.1 (4H, m; pyrrolidinone-CH; OCH₃), 4.2–4.3(2H, m; OCH₂), 6.1 (1H, br s; NH), 7.3 (1H, s; ArH), 7.4 (1H, dd; ArH),7.5 (1H, dd; ArH), 7.9 (1H, d; ArH), 8.0 (1H, br s; ArH), 8.2 (1H, d;ArH), 8.6 (1H, s; ArH) and 8.9 (1H, dd; ArH)

m/z (ESP+) 417 (MH⁺, 100%)

EXAMPLE 200

To a solution of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (100 mg,0.31 mmol), (prepared as described for the starting material in Example9), in DMF (10 ml) was added potassium carbonate (124 mg, 0.9 mmol,3eq.) followed by 2-hydroxycarbazole (66 mg, 0.36 mmol, 1.2eq.) and thereaction heated at 100° C. for 4 hours. The DMF was removed in vacuo,the residue dissolved in dichloromethane and placed onto a 2 g SCXion-exchange column. Elution with dichloromethane, followed by 20%methanol/dichloromethane then 20% methanol/dichloromethane+3% ammoniumhydroxide, gave the crude product as a brown solid. Further purificationby silica bond elut chromatography eluting with dichloromethane to 15%methanol/dichloromethane+1% ammonium hydroxide, followed by triturationwith ether gave4-(9H-carbazol-2-yloxy)-6-methoxy-7–3-(pyrrolidin-1-yl)propoxy)quinazoline(31 mg, 22%) as a white solid.

¹H NMR Spectrum: d_(H) (300 MHz, DMSO-d₆) 1.7 (4H, m;2×pyrrolidine-CH₂), 2.0 (2H, t; OCH₂CH₂), 2.5 (4H, m;2×pyrrolidine-NCH₂), 2.6 (2H, t; NCH₂), 4.0 (3H, s; OCH₃), 4.2 (2H, t;OCH₂), 7.1 (1H, br d; ArH), 7.2 (1H, t; ArH), 7.3–7.4 (3H, m; 3×ArH),7.5 (1H, br d; ArH), 7.6 (1H, s; ArH), 8.1–8.2 (2H, m; 2×ArH), 8.5 (1H,s; ArH), 11.3 (1H, s; carbazole NH)

m/z (ESP+) 469 (MH⁺, 100%)

EXAMPLE 201

To a solution of 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98mg, 0.32 mmol),2-((N-(3,6-dichloropyridazin-4-yl)-N-methyl)amino)ethanol (107 mg, 0.48mmol), (prepared as described for the starting material in Example 142),triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (1 ml) andDMF (0.5 ml) cooled at 4° C. was added a solution of diethylazodicarboxylate (101 μl, 0.64 mmol) in methylene chloride (0.4 ml). Themixture was stirred for 12 hours at 4° C. and overnight at ambienttemperature. The precipitate was filtered, washed with ether and driedunder vacuum to give7-(2-((N-(3,6-dichloropyridazin-4-yl)-N-methyl)amino)ethoxy)4-(indol-5-ylamino)-6-methoxyquinazoline(72 mg, 44%).

MS-ESI: 510–512 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 3.12 (s, 3H); 3.85 (s, 3H); 4.1 (t, 2H); 4.45(t, 2H); 6.45 (s, 1H); 7.2 (s, 1H); 7.3 (s, 1H); 7.35 (m, 2H);7.42 (d,1H);7.8 (s, 1H); 7.85 (s, 1H); 8.35 (s, 1H); 9.45 (s, 1H)

The starting material was prepared as follows:

A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (5 g, 16.6mmol), (prepared as described for the starting material in Example 1),5-aminoindole (2.4 g, 18.2 mmol) in isopropanol (60 ml) containing 5Nhydrogen chloride in isopropanol (260 μl, 1.6 mmol) was refluxed for 90minutes. After cooling the volatiles were removed under vacuum. Thesolid was triturated with isopropanol, filtered, washed with isopropanolfollowed by ether and dried under vacuum to give7-benzyloxy-4(indol-5-ylamino)-6-methoxyquinazoline hydrochloride (6.9g, 96%).

¹H NMR Spectrum: (DMSOd₆) 4.05 (s, 3H); 5.35 (s, 2H); 6.5 (s, 1H); 7.3(d, 1H); 7.4–7.65 (m, 9H); 7.8(s, 1H);8.3(s, 1H);8.7 (s, 1H)

A solution of give 7-benzyloxy-4-(indol-5-ylamino)-6-methoxyquinazolinehydrochloride (10 g, 23.1 mmol) in methanol (300 ml) and DMF (100 ml)containing ammonium formate (22gr, 347 mmol) and 10% palladium oncharcoal (1 g) was stirred overnight at ambient temperature. Thesolution was filtered over celite and washed with DMF followed bymethanol. The filtrate was evaporated. The residue was dissolved inaqueous ammonia 2 mM (300 ml) and stirred for 15 minutes. The solid wasfiltered, washed with water followed by ethyl acetate and ether anddried under vacuum at 50° C. for 2 days. The solid was purified bycolumn chromatography eluting with methanol/methylene chloride (1/9).The volatiles were removed under vacuum and the solid was left undervacuum at 70° C. for 2 days to give7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (6.8 g, 97%)

MS-ESI: 307 [MH]+

¹H NMR Spectrum: (DMSOd₆) 3.98 (s, 3H); 6.42 (s, 1H); 7.0 (s, 1H);7.3–7.45 (m, 3H); 7.85 (s, 2H); 8.28 (s, 1H); 9.35 (s, 1H); 10.25 (br s,1H); 11.05 (s, 1H)

EXAMPLES 202–204

Using an analogous procedure to that described in Example 201,7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline, (prepared asdescribed for the starting material in Example 201), was used in thesynthesis of the compounds described in Table XI.

TABLE XI

Example MS-ESI number Weight (mg) Yield % [MH]⁺ Note R 202 83 59 441 a

203 91 72 398 b

204 76 55 432 c

a 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline was reacted with2-(N-methyl-N-(4-pyridyl)amino)ethanol (73 mg), (EP 0359389), to give4-(indol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 3.08(s, 3H); 3.9(t, 2H); 3.95(s, 3H); 4.35(t,2H); 6.45(s, 1H); 6.75(d, 2H); 7.15(s, 1H); 7.35(m, 2H); 7.4(d, 1H);7.85(s, 1H); 7.9(s, 1H); 8.15(d, 2H); 8.38(s, 1H); 9.45(s, 1H) b7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline was reacted with3-hydroxymethyl pyridine (53 mg) to give4-(indol-5-ylamino)-6-methoxy-7-((3-pyridyl)methoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 4.0(s, 3H); 5.35(s, 2H); 6.42(s, 1H); 7.3–7.55(m,5H); 7.8–8.0(m, 3H); 8.4(s, 1H); 8.6(d, 1H); 8.75(s, 1H); 9.5(s, 1H) c7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline was reacted with5-(2-hydroxyethyl)-4-methylthiazole (69 mg) to give4-(indol-5-ylamino)-6-methoxy-7-(2-(4-methyl-1,3-thiazol-5-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.45(s, 3H); 3.32(t, 2H); 3.95(s, 3H); 4.32(t,2H); 6.45(s, 1H); 7.15(s, 1H); 7.3–7.45(m, 3H); 7.85(s, 1H); 7.9(s, 1H);8.35(s, 1H); 8.85(s, 1H); 9.45(s, 1H)

EXAMPLE 205

To a solution of7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32mmol), 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol), (prepared asdescribed for the starting material in Example 60), triphenylphosphine(168 mg, 0.64 mmol) in methylene chloride (1 ml) and DMF (0.5 ml) cooledat 4° C. was added a solution of diethyl azodicarboxylate (101 μl; 0.64mmol) in methylene chloride (0.4 ml). The mixture was stirred for 12hours at 4° C. and overnight at ambient temperature. The mixture waspoured onto a column of silica (IST isolute® 10 g of silica) and waseluted with methylene chloride (15 ml) followed by 5% methanol inmethylene chloride (45 ml) followed by 5% methanol (saturated withammonia) in methylene chloride (30 ml) followed by 10% methanol(saturated with ammonia) in methylene chloride (45 ml) followed by 15%methanol (saturated with ammonia) in methylene chloride (30 ml). Thefractions containing the expected product were evaporated to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline(63 mg, 44%).

MS-ESI: 448 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.0 (m, 2H); 2.4 (s, 3H); 2.3–2.6 (m, 6H); 3.6(t, 4H); 3.95 (s, 3H); 4.2 (t, 2H); 6.12 (s, 1H); 7.12 (s, 1H); 7.3 (brs, 2H); 7.7 (s, 1H); 7.85 (s, 1H); 8.35 (s, 1H); 9.4 (s, 1H)

The starting material was prepared as follows:

A solution of 2-methyl-5-nitroindole (1 g, 5.7 mmol) in ethanol (25 ml)and THF (25 ml) containg 10% palladium on charcoal (128 mg) washydrogenated until uptake of hydrogen ceased. The mixture was filteredand the filtrate was evaporated to give 5-amino-2-methylindole (830 mg,quant.).

¹H NMR Spectrum: (DMSOd₆) 2.3 (s, 3H): 4.3 (br s, 2H); 5.8 (s, 1H); 6.35(d, 1H); 6.55 (s, 1H); 6.95 (d, 1H); 10.35 (br s, 1H)

Using an analogous procedure to that described for the synthesis of thestarting material in Example 201,7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.6 mmol), (prepared asdescribed for the starting material in Example 1), was reacted with5-amino-2-methylindole (1.07 g, 7.3 mmol) to give7-benzyloxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazolinehydrochloride (2.9 g, quanti.).

MS-ESI: 411 [MH]+

¹H NMR Spectrum: (DMSOd₆) 2.41 (s, 3H); 4.01 (s, 3H); 5.33 (s, 2H); 6.18(s, 1H); 7.25 (d, 1H); 7.3–7.7 (m, 8H); 8.3 (s, 1H); 8.7 (s, 1H); 11.1(s, 1H); 11.4 (s, 1H)

Using an analogous procedure to that described for the synthesis of thestarting material in Example 201,7-benzyloxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazolinehydrochloride (2.87 g, 6.4 mmol) was reacted with ammonium formate (6 g,9.6 mmol) to give7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (1.91 g,93%).

MS-ESI: 321 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 3.95 (s, 3H); 6.12 (s, 1H); 7.0(s, 1H); 7.25 (s, 1H); 7.7 (s, 1H); 7.85 (s, 1H); 8.3 (s, 1H); 9.35 (s,1H); 10.2 (br s, 1H); 10.9 (s, 1H)

EXAMPLES 206–207

Using an analogous procedure to that described for Example 205,7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline, (prepared asdescribed for the starting material in Example 205), was used in thesynthesis of the compounds described in Table XII.

TABLE XII

Example MS-ESI Number Weight (mg) Yield % [MH]⁺ Note R 206 65 41 496 a

207 62 45 b

a 7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (98 mg) wasreacted with 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg), (preparedas described for the starting material in Example 5), to give7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.0(m, 2H); 2.4(s, 3H); 2.7(t, 2H); 2.95(m,4H); 3.15(m, 4H); 3.95(s, 3H); 4.2(t, 2H); 6.15(s, 1H); 7.18(s, 1H);7.28(m, 2H); 7.7(s, 1H); 7.85(s, 1H); 8.35(s, 1H); 9.4(s, 1H) b7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (98 mg) wasreacted with 1-(2-hydroxyethyl)piperidine (62 mg) to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(2-piperidinoethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.4(m, 2H); 1.45–1.6(m, 4H); 2.42(s, 3H);2.45(br s, 4H); 2.75(t, 2H); 3.95(s, 3H); 4.25(t, 2H); 6.15(s, 1H);7.15(s, 1H); 7.25(br s, 2H); 7.7(s, 1H); 7.88(s, 1H); 8.35(s, 1H);9.4(s, 1H)

EXAMPLE 208

Using an analogous procedure to that described in Example 205,7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol),(prepared as described for the starting material in Example 201), wasreacted with 3-(1,2,3-triazol-1-yl)propan-1-ol (61 mg, 0.48 mmol) togive4-(indol-5-ylamino)-6-methoxy-7-(3-(1,2,3-triazol-1-yl)propoxy)quinazoline(56 mg, 42%).

MS-ESI: 416 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.4 (m, 2H); 4.0 (s, 3H); 4.2 (t, 2H); 4.65(t, 2H); 6.45 (s, 1H); 7.15 (s, 1H); 7.35 (m, 2H); 7.42 (d, 1H); 7.75(s, 1H); 7.88 (s, 1H); 7.9 (s, 1H); 8.2 (s, 1H); 8.38 (s, 1H); 9.42 (s,1H)

The starting material was prepared as follows:

A mixture of 1,2,3-triazole (5 g, 72.4 mmol) and ethyl acrylate (7.8 ml,72.4 mmol) containing pyridine (50 drops) was heated at 90° C. for 4hours. After cooling, the volatiles were removed under vacuum and theresidue was purified by column chromatography eluting with methylenechloride/ether to give ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96 g,73%).

¹H NMR Spectrum: (CDCl₃) 1.25 (t, 3H); 2.95 (t, 2H); 4.15 (q, 2H); 4.7(t, 2H); 7.65 (s, 1H); 7.7 (s, 1H)

A solution of ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96 g, 53 mmol)in THF (50 ml) was added dropwise to a suspension of lithium aluminiumhydride (3 g, 79 mmol) in THF (250 ml) cooled at 0° C. After stirringfor 1 hour at 5° C., the mixture was stirred for 1 hour at ambienttemperature. The mixture was cooled at 0° C. and 4N sodium hydroxide (30ml) was added dropwise. The mixture was filtered and the solid waswashed with THF followed by ethyl acetate. The filtrate was dried(MgSO₄) and evaporated. The residue was purified by columnchromatography, eluting with methylene chloride/methanol (94/6) to give3-(1,2,3-triazol-1-yl)propan-1-ol (6.2 g, 92%).

¹H NMR Spectrum: (CDCl₃): 2.1–2.2 (m, 3H); 3.65 (m, 2H); 4.6 (t, 2H);7.6 (s, 1H); 7.72 (s, 1H)

EXAMPLES 209–216

Using an analogous procedure to that described in Example 208,7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline, (prepared asdescribed for the starting material in Example 201), was used in thesynthesis of the compounds described in Table XIII.

TABLE XIII

Example MS-ESI Number Weight (mg) Yield % [MH]⁺ Note R 209 77 57 422 a

210 64 45 446 b

211 76 49 482 c

212 70 48 462 d

213 85 59 447 e

214 62 54 365 f

215 71 54 409 g

216 73 55 418 h

a 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (64 mg), (prepared asdescribed for the starting material in Example 59), to give4-(indol-5-ylamino)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.35(s, 3H); 2.68(t, 2H); 2.82(t, 2H); 3.25(s,3H); 3.5(t, 2H); 3.97(s, 3H); 4.22(t, 2H), 6.45(s, 1H); 7.18(s, 1H);7.3–7.45(m, 3H); 7.88(m, 2H); 8.35(s, 1H); 9.42(s, 1H) b7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 1-(3-hydroxypropyl)pyrrolidin-2,5-dione (76 mg) to give7-(3-(2,5-dioxopyrrolidin-1-yl)propoxy)-4-(indol-5-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.05(m, 2H); 2.65(s, 3H); 3.6(t, 2H); 3.98(s,2H); 4.15(t, 2H); 6.45(s, 1H); 7.1(s, 1H); 7.3–7.45(m, 3H); 8.7(s, 1H);8.8(s, 1H); 8.35(s, 1H); 9.45(s, 1H) The starting material was preparedas follows: A solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) and3-bromopropan-1-ol (6.85 ml, 76 mmol) in acetonitrile (80 ml) containingpotassium carbonate (14 g, 100 mmol) was refluxed overnight. Aftercooling, the mixture was filtered and the filtrate was evaporated. Theresidue was dissolved in methylene chloride and purified by columnchromatography, eluting with ethylacetate/petroleum ether (4/1). Afterevaporation of the volatiles, the residue was distilled at 100–125° C.under about 0.1 mm Hg to give 1-(3-hydroxypropyl)pyrrolidin-2,5-dione(2.6 g, 34%). ¹H NMR Spectrum: (CDCl₃) 1.8(m, 2H); 2.52(t, 1H); 2.78(s,4H); 3.58(q, 2H); 3.7(t, 2H) c7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg), (prepared asdescribed for the starting material in Example 5), to give7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.0(m, 2H); 2.7(t, 2H); 2.95(br s, 4H);3.15(br s, 4H); 3.97(s, 3H); 4.2(t, 2H); 6.45(s, 1H); 7.2(s, 1H);7.3–7.5(m, 3H); 7.9(2s, 2H); 8.35(s, 1H); 9.42(s, 1H) d7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (83 mg) togive4-(indol-5-ylamino)-6-methoxy-7-(3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.22(m, 2H); 3.3(m, 2H); 3.65(s, 3H); 3.95(s,3H); 4.25(t, 2H); 6.45(s, 1H); 7.15(s, 1H); 7.3–7.45(m, 3H); 7.88(s,1H); 8.0(s, 1H); 8.35(s, 1H); 8.58(s, 1H); 9.45(s, 1H) The startingmaterial was prepared as follows: A solution of4-methyl-4-H-1,2,4-triazole-3-thiol (1.72 g, 15 mmol) and3-bromopropan-1-ol (1.39 g, 10 mmol) in DMF (10 ml) containing potassiumcarbonate (1.57 g, 14 mmol) was heated at 40° C. for 30 minutes. Themixture was then partitioned between saturated ammonium chloride andethyl acetate. The aqueous layer was evaporated to dryness and theresidue was triturated with ethyl acetate and methylene chloride. Thesuspension was filtered and the filtrate was dried (MgSO₄) andevaporated. The residue was purified by column chromatography elutingwith methylene chloride/methanol (9/1) to give3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (510 mg, 30%).¹H NMR Spectrum: (CDCl₃) 2.02(m, 2H); 3.45(t, 2H); 3.55(s, 3H); 3.75(t,2H); 8.15(s, 1H) e 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline(98 mg) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (76 mg),(prepared as described for the starting material in Example 133), togive4-(indol-5-ylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.0(m, 2H); 2.2(s, 3H); 2.25–2.55(m, 10H);4.0(s, 3H); 4.2(t, 2H); 6.45(s, 1H); 7.15(s, 1H); 7.35(m, 2H); 7.42(d,1H); 7.88(br s, 2H); 8.38(s, 1H); 9.42(s, 1H) f7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 2-methoxyethanol (37 mg) to give4-(indol-5-ylamino)-6-methoxy-7-(2-methoxyethoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 3.4(s, 3H); 3.75(t, 2H); 3.98(s, 3H); 4.38(t, 2H);6.45(s, 1H); 7.18(s, 1H); 7.35(m, 2H); 7.42(d, 1H); 7.85(s, 1H); 7.9(s,1H); 8.38(s, 1H); 9.5(s, 1H) g7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 2-(2-methoxyethoxy)ethanol (58 mg) to give4-(indol-5-ylamino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 3.3(s, 3H); 3.5(t, 2H); 3.65(t, 2H); 3.85(t,2H); 4.0(s, 3H); 4.28(t, 2H); 6.45(s, 1H); 7.18(s, 1H); 7.35(m, 2H);7.45(d, 1H); 7.88(s, 1H); 7.9(s, 1H); 8.35(s, 1H); 9.45(s, 1H) h7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 1-(2-hydroxyethyl)piperidine (62 mg) to give4-(indol-5-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 1.3–1.6(m, 6H); 2.5(br s, 4H); 2.7(t, 2H); 3.98(s,3H); 4.25(t, 2H); 6.45(s, 1H); 7.18(s, 1H); 7.35(m, 2H); 7.42(d, 1H);7.9(br s, 2H); 8.38(s, 1H); 9.42(s, 1H)

EXAMPLE 217–223

Using an analogous procedure to that described in Example 205,7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline was used in thesynthesis of the compounds described in Table XIV.

The starting material was prepared as follows:

Using an analogous procedure to that described for the preparation ofthe starting material in Example 201, 6-nitroindole (500 mg, 3 mmol) washydrogenated to give 6-aminoindole (395 mg, quant.).

¹H NMR Spectrum: (DMSOd₆) 6.41 (s, 1H); 6.6 (dd, 1H); 6.63 (s, 1H); 7.0(t, 1H); 7.4 (d, 1H); 7.87 (br s, 1H)

Using an analogous procedure to that described for the preparation ofthe starting material in Example 201,7-benzyloxy-4-chloro-6-methoxyquinazoline (2.5 g, 8.3 mmol), (preparedas described for the starting material in Example 1), was reacted with6-aminoindole (1.5 g, 11.4 mmol) to give7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride (3.18g, 89%).

MS-ESI: 397 [MH]+

¹H NMR Spectrum: (DMSOd₆) 4.02 (s, 3H); 5.35 (s, 2H); 6.5 (s, 1H); 7.25(dd, 1H); 7.35–7.6 (m, 5H); 7.63 (d, 1H); 7.72 (s, 1H); 8.3 (s, 1H);8.75 (s, 1H); 11.3 (br s, 1H)

Using an analogous procedure to that described for the preparation ofthe starting material in Example 201,7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride wastreated with ammonium formate (655 mg, 10.4 mmol) to give7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (162 mg, 76%).

MS-ESI: 307 [MH]+

¹H NMR Spectrum: (DMSOd₆) 4.0 (s, 3H); 6.4 (s, 1H); 7.0 (s, 1H); 7.3 (m,2H); 7.5 (d, 1H); 7.85 (s, 1H); 8.0 (s, 1H); 8.35 (s, 1H); 9.35 (s, 1H);11.05 (s, 1H)

TABLE XIV

Example MS-ESI number Weight (mg) Yield % [MH]⁺ Note R 217 46 35 416 a

218 57 37 482 b

219 37 25 462 c

220 38 29 418 d

221 10 7 418 e

222 94 61 483 f

223 56 44 398 g

a 7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-(1,2,3-triazol-1-yl)propan-1-ol (61 mg), (prepared as describedfor the starting material in Example 208), to give4-(indol-6-ylamino)-6-methoxy-7-(3-(1,2,3-triazol-1-yl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.42(t, 2H); 4.02(s, 3H); 4.2(t, 2H); 4.62(t,2H); 6.42(s, 1H); 7.15(s, 1H); 7.3(m, 2H); 7.55(d, 1H); 7.75(s, 1H);7.92(s, 1H); 8.02(s, 1H); 8.2(s, 1H); 8.42(s, 1H); 9.45(s, 1H) b7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg), (prepared asdescribed for the starting material in Example 5), to give7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-6-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.0(m, 2H); 2.7(t, 2H); 2.95(br s, 4H);3.12(br s, 4H); 4.0(s, 3H); 4.2(t, 2H); 6.42(s, 1H); 7.2(s, 1H); 7.3(m,2H); 7.55(d, 1H); 7.9(s, 1H); 8.02(s, 1H); 8.42(s, 1H); 9.48(s, 1H) c7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (83 mg),(prepared as described for the starting material in Example 212), togive4-(indol-6-ylamino)-6-methoxy-7-(3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.22(t, 2H); 3.3(t, 2H); 3.6(s, 3H); 4.0(s,3H); 4.28(t, 2H); 6.4(s, 1H); 7.18(s, 1H); 7.3(m, 2H); 7.53(d, 1H);7.9(s, 1H); 8.02(s, 1H); 8.42(s, 1H); 8.58(s, 1H); 9.45(s, 1H) d7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 1-(2-hydroxyethyl)piperidine (62 mg) to give4-(indol-6-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 1.3–1.6(m, 6H); 2.5(br s, 4H); 2.75(t, 2H); 4.0(s,3H); 4.25(t, 2H); 6.42(s, 1H); 7.2(s, 1H); 7.3(m, 2H); 7.55(d, 1H);7.9(s, 1H); 8.02(s, 1H); 8.42(s, 1H); 9.45(s, 1H) e7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 1-(3-hydroxypropyl)pyrrolidine (62 mg) to give4-(indol-6-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.The starting material was prepared as follows: A solution of pyrrolidine(50 g, 0.7 mol) and 3-chloropropan-1-ol (66.15 g, 0.7 mol) inacetonitrile (1 l) containing potassium carbonate (145 g, 1.05 mol) wasrefluxed for 20 hours. After cooling, the mixture was filtered, thesolid was washed with acetonitrile and the filtrate was evaporated. Theresidue was distilled at about 130° C. under about 70 mmHg to give1-(3-hydroxypropyl)pyrrolidine (62.1 g, 69%). MS-ESI: 130 [MH]+ ¹H NMRSpectrum: (CDCl₃) 1.6–1.8(m, 6H); 2.55(br s, 4H); 2.75(t, 2H); 3.85(t,2H); 5.2–5.8(br s, 1H) f7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93 mg)to give7-(3-((N-(2,6dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-4-(indol-6-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.08(m, 2H); 2.22(s, 6H); 2.95(s, 3H); 3.6(t,2H); 4.05(s, 3H); 4.15(t, 2H); 6.35(s, 2H); 6.42(s, 1H); 7.15(s, 1H);7.3(m, 2H); 7.55(d, 1H); 7.92(s, 1H); 8.02(s, 1H); 8.4(s, 1H); 9.45(s,1H) The starting material was prepared as follows: A solution of4-chloro-2,6-dimethylpyridine (2.12 g, 15 mmol) and3-(N-methylamino)-propan-1-ol (4 g, 45 mmol) containing 2N hydrogenchloride in ether (10 drops) was heated at 140° C. for 1 hour. Themixture was diluted with water (10 ml) and poured onto a suspension ofMgSO₄ (125 g) in ethyl acetate (200 ml). The mixture was filtered. Thefiltrate was evaporated and the residue was triturated with ether. Thesolid was filtered and dried under vacuum to give3-((N-2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (1.76 g, 61%).MS-EI: 194 [M.]+ ¹H NMR Spectrum: (CDCl₃) 1.75–1.95(m, 2H); 2.4(s, 6H);3.0(s, 3H); 3.48(t, 2H); 3.7(t, 2H); 6.25(s, 2H) g7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 3-hydroxymethyl pyridine (53 mg) to give4-(indol-6-ylamino)-6-methoxy-7-((3-pyridyl)methoxy)quinazoline. ¹H NMRSpectrum: (DMSOd₆) 4.02(s, 3H); 5.35(s, 2H); 6.42(s, 1H); 7.22–7.4(m,3H); 7.5(m, 1H); 7.55(d, 1H); 7.95(s, 1H); 7.97(d, 1H); 8.0(s, 1H);8.42(s, 1H); 8.6(d, 1H); 8.78(s, 1H); 9.5(s, 1H)

EXAMPLE 224

Using an analogous procedure to that described in Example 208,7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol),(prepared as described for the starting material in Example 201), wasreacted with (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (68 mg, 0.48 mmol),(prepared as described for the starting material in Example 129). Afterevaporation of the fractions containing the expected product, theresidue was triturated with isopropanol (1 ml) containing 6.2 N hydrogenchloride in isopropanol (100 μl). After stirring at ambient temperaturefor 10 minutes, ether (500 μl) was added. The precipitate was filteredand washed several times with ether to give4-(indol-5-ylamino)-6-methoxy-7-((E)4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazolinehydrochloride (14 mg, 10%).

MS-ESI: 430 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.85–2.7 (br s, 4H); 2.95–3.1 (br s, 2H); 3.0(m, 2H); 3.4–3.5 (m, 2H); 3.8 (d, 2H); 4.0 (s, 3H); 4.8 (d, 2H); 6.0–6.3(m, 2H); 6.5 (s, 1H); 7.2–7.53 (m, 4H); 7.75 (s, 1H); 8.25 (s, 1H); 8.8(br s, 1H)

EXAMPLE 225

7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline, (prepared asdescribed for the starting material in Example 201), was treated asfollows. After purification by chromatography and evaporation of thesolvent, the residue was triturated in a solution of isopropanol (1 ml)containing 6.2 N hydrogen chloride in isopropanol (100 μl). Afterstirring for 10 minutes at ambient temperature, ether (500 μl) wasadded. The solid was filtered and dried under vacuum to give7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline hydrochloride.

Using an analogous procedure to that described in Example 224,7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline hydrochloride wasused in the synthesis of the compounds described in Table XV.

TABLE XV

Example MS-ESI Number Weight (mg) Yield % [MH]⁺ Note R 225 77 50 483 a

a 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline hydrochloride (98mg) was reacted with3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93 mg),(prepared as described for the starting material in Example 222), togive7-(3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-4-(indol-5-ylamino)-6-methoxyquinazoline.¹H NMR Spectrum: (DMSOd₆) 2.2(m, 2H); 2.5(2br s, 6H); 3.2(s, 3H); 3.8(t,2H); 4.1(s, 3H); 4.25(t, 2H); 6.52(s, 1H); 6.75(br s, 1H); 6.9(br s,1H); 7.35(dd, 1H); 7.45(br s, 2H); 7.5(d, 1H); 7.8(s, 1H); 8.4(s, 1H);8.75(s, 1H)

EXAMPLE 226

Using an analogous procedure to that described in Example 224,7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline, (prepared asdescribed for the starting material in Example 217), (98 mg, 0.32 mmol)was reacted with 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol),(prepared as described for the starting material in Example 60), to give4-(indol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazolinehydrochloride (26 mg, 19%).

MS-ESI: 434 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.35 (m, 2H); 3.15 (m, 2H); 3.3 (t,2H); 3.52 (d, 2H); 3.8 (t, 2H); 4.0 (d, 2H); 4.1 (s, 3H); 4.3 (t, 2H);6.5 (s, 0.5H, partly exchanged); 7.3 (d, 1H); 7.4 (s, 1H); 7.45 (s, 1H);7.65 (d, 1H); 7.75 (s, 1H); 8.3 (s, 1H); 8.75 (s, 1H)

EXAMPLES 227–229

Using an analogous procedure to that described in Example 226,7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline, (prepared asdescribed for the starting material in Example 217), was used in thesynthesis of the compounds described in Table XVI.

TABLE XVI

Example MS-ESI number Weight (mg) Yield % [MH]⁺ Note R 227 24 17 441 a

228 14 10 430 b

229 15 10 447 c

a 7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 2-((N-methyl-N-(4-pyridyl))amino)ethanol (73 mg), (EP 0359389A1),to give4-(indol-6-ylamino)-6-methoxy-7-(2-((N-methyl-N-(4-pyridyl))amino)ethoxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆) 3.3(s, 3H); 4.0(s, 3H); 4.18(t,2H); 4.45(t, 2H); 6.5(s, 1H); 7.35(d, 1H); 7.35–7.5(m, 4H); 7.62(d, 1H);7.75(s, 1H); 8.3(d, 2H); 8.4(s, 1H); 8.75(s, 1H) b7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (68 mg, 0.48 mmol), (preparedas described for the starting material in Example 129) to give4-(indol-6-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆) 1.8–2.1(m, 4H); 2.9–3.1(m, 2H);3.4–3.5(br s, 2H); 3.87(d, 2H); 4.05(s, 3H); 4.9(d, 2H); 6.1(m, 1H);6.3(m, 1H); 6.5(s, 1H); 7.25(d, 1H); 7.45(m, 2H); 7.65(d, 1H); 7.75(s,1H); 8.3(s, 1H); 8.8(s, 1H) c7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was reactedwith 1-(3-hydroxypropyl)-4-methylpiperazine (76 mg), (prepared asdescribed for the starting material in Example 133), to give4-(indol-6-ylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolinehydrochloride.

EXAMPLE 230

Using an analogous procedure to that described in Example 224,7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32mmol), (prepared as described for the starting material in Example 205),was reacted with 1-(3-hydroxypropyl)-2-methylimidazole (67 mg, 0.48mmol), (EP 0060696 A1), to give6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)-4-(2-methylindol-5-ylamino)quinazoline(53 mg, 37%).

MS-ESI: 443 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.42 (s, 3H); 2.62 (s, 3H); 4.03 (s, 3H); 4.3(t, 2H); 4.35 (t, 2H); 6.2 (s, 1H); 7.22 (d, 1H); 7.35 (d, 1H); 7.45 (s,1H); 7.6 (dd, 1H); 7.65 (dd, 1H); 7.7 (s, 1H); 8.35 (s, 1H); 8.75 (s,1H)

EXAMPLES 231–235

Using an analogous procedure to that described in Example 224,7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32mmol), (prepared as described for the starting material in Example 205),was used in the synthesis of the compounds described in Table XVII.

TABLE XVII

Example MS-ESI number Weight (mg) Yield % [MH]⁺ Note R 231 49 31 497 a

232 25 18 444 b

233 23 15 476 c

234 33 22 461 d

235 26 19 423 e

a 7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg)was reacted with3-((N-2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93 mg),(prepared as described for the starting material in Example 222), togive7-(3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.2(m, 2H); 2.4(s, 6H); 2.45(s, 3H); 3.15(s,3H); 3.75(t, 2H); 4.02(s, 3H); 4.25(t, 2H); 6.2(s, 1H); 6.72(br s, 1H);6.85(br s, 1H); 7.2(dd, 1H); 7.3–7.4(m, 2H); 7.62(s, 1H); 8.3(s, 1H);8.7(s, 1H) b 7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline(102 mg) was reacted with (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (68 mg,0.48 mmol), (prepared as described for the starting material in Example129) to give6-methoxy-4-(2-methylindol-5-ylamino)-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 1.8–2.1(m, 4H); 2.4(s, 3H); 2.9–3.1(m, 2H);3.4–3.6(m, 2H); 3.9(d, 2H); 4.05(s, 3H); 4.9(d, 2H); 6.1(m, 1H); 6.2(s,1H); 6.3(d, t, 1H); 7.2(m, 1H); 7.37(d, 1H); 7.4(s, 1H); 7.32(s, 1H);8.3(s, 1H); 8.75(s, 1H) c7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg) wasreacted with 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol(83 mg), (prepared as described for the starting material in Example212), to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.25(m, 2H); 2.45(s, 3H); 3.35(t, 2H); 3.65(s,3H); 4.05(s, 3H); 4.35(t, 2H); 6.2(s, 1H); 7.2(d, 1H); 7.35(s, 1H);7.37(d, 1H); 7.62(s, 1H); 8.25(s, 1H); 8.75(s, 1H); 8.9(s, 1H) d7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (103 mg) wasreacted with 1-(3-hydroxypropyl)-4-methylpiperazine (76 mg), (preparedas described for the starting material in Example 133), to give6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline.e 7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg)was reacted with 2-(2-methoxyethoxy)ethanol to give6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-ylamino)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.45(s, 3H); 3.28(s, 3H); 3.5(t, 2H), 3.65(t,2H); 3.9(t, 2H); 4.02(s, 3H); 4.33(t, 2H); 6.2(s, 1H); 7.2(d, 1H);7.4(m, 2H); 7.63(s, 1H); 8.28(s, 1H); 8.73(s, 1H)

EXAMPLE 236

A solution of4-chloro-6-methoxy-7-((1-cyanomethylpiperidin-4-yl)methoxy)quinazoline(200 mg, 0.58 mmol) and 5-hydroxyindole (85 mg, 0.63 mmol) in DMF (3 ml)containing cesium carbonate (282 mg, 0.86 mmol) was stirred at 90° C.for 90 minutes. After cooling, the mixture was poured onto water (25ml). The precipitate was filtered, dried under vacuum and purified byreverse phase column chromatography on silica (kromasil® C18) elutingwith methanol/water (1% acetic acid) (1/1). The fractions containing theexpected product were combined and evaporated to give7-((1-cyanomethyl)piperidin-4-ylmethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(44 mg, 17%).

MS-ESI: 444 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.7 (m, 2H); 2.15 (d, 2H); 2.2–2.35(m, 1H); 3.20 (t, 2H); 3.65 (d, 2H);4.1 (s, 3H); 4.25 (d, 2H); 4.62 (s,2H); 6.5 (s, 0.5H, partly exchanged); 7.1 (dd, 1H); 7.5 (s, 1H); 7.5–7.6(m, 3H); 7.85 (s, 1H); 9.1 (s, 1H)

The starting material was prepared as follows:

To a suspension of6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-onehydrochloride (34 g, 84 mmol), (prepared as described for the startingmaterial in Example 12), in water cooled at 0° C. was added 1N sodiumhydroxide until the mixture was at pH8. The solution was extracted withtrichloromethane and the organic layer was dried (MgSO₄), filtered andevaporated to give6-methoxy-7-piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(29 g).

To a solution of6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(28.9 g, 72 mmol) and aqueous formaldehyde 12 M (11.95 ml, 141 mmol) inmethanol/THF (1/1) (580 ml) was added sodium cyanoborohydride (5.7 g, 86mmol) in portions. After stirring for 90 minutes at ambient temperature,the volatiles were removed under vacuum and the residue was partitionedbetween methylene chloride and water. The organic layer was separated,dried (MgSO₄) and evaporated. The residue was dissolved in methanolsaturated with ammonia (500 ml). The mixture was stirred for 36 hours atambient temperature. The volatiles were removed under vacuum. Theresidue was triturated with a mixture ether/methylene chloride,filtered, washed with ether and dried under vacuum. The solid wasdissolved in thionyl chloride (180 ml) and DMF (1.8 ml) was added. Afterstirring at 80° C. for 75 minutes the volatiles were removed undervacuum. The residue was azeotroped with toluene twice and the solid waspartitioned between methylene chloride and water and the pH of theaqueous layer was adjusted to 9 with 2N sodium hydroxide. The organiclayer was dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography on aluminium oxide eluting with methylenechloride, followed by methylene chloride/ethyl acetate (70/30 followedby 50/50) followed by ethyl acetate and ethyl acetate/methanol (80/20)to give 4-chloro-6-methoxy-7((1-methylpiperidin-4-yl)methoxy)quinazoline(11.2 g) (identical to the starting material prepared in Example 10) and4-chloro-6-methoxy-7-((1-(cyanomethyl)piperidin-4-yl)methoxy)quinazoline(2.55 g).

MS-ESI: 347 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.42 (m, 2H); 1.85 (d, 2H); 1.8–1.9 (m, 1H);2.2 (t, 2H); 2.85 (d, 2H); 3.75 (s, 2H); 4.05 (s, 3H); 4.15 (d, 2H);7.42 (s, 1H); 7.5 (s, 1H); 8.9 (s, 1H)

EXAMPLE 237

A solution of4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2 gr,6.22 mmol), (prepared as described for the starting material in Example10), and 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46 mmol) in DMF(30 ml) containing potassium carbonate (1.28 g, 9.33 mmol) was stirredat 95° C. for 2 hours. After cooling, the volatiles were removed undervacuum and the residue was triturated with ether, filtered and driedunder vacuum. The residue was purified by column chromatography elutingwith methanol/methylene chloride (1/9) followed by methanol/methanolsaturated with ammonia/methylene chloride (20/1/79 followed by 20/5/75).The fractions containing the expected product were combined andevaporated. The solid was triturated with methanol, filtered and driedunder vacuum to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline(1.95 g, 69%).

MS-ESI: 451 [MH]⁺

¹H NMR Spectrum (DMSOd₆) 1.4 (m, 2H); 1.8 (d, 2H); 1.7–1.9 (m, 1H); 1.9(t, 2H); 2.2 (s, 3H); 2.45 (s, 3H); 2.8 (d, 2H); 4.02 (s, 3H); 4.1 (d,2H); 6.25 (s, 1H); 7.0 (dd, 1H); 7.2 (d, 1H);7.4(s, 1H);7.62(s,1H);8.5(s, 1H)

Elemental analysis: Found C 64.2 H 6.5 N 11.7 C₂₅H₂₇FN₄O₃ 0.91methanolRequires C 63.9 H 6.4 N 11.5% 0.08CH₂Cl₂ 0.1H₂O

The starting material was prepared as follows:

To a solution of 2-fluoro-4-nitroanisole (9.9 g, 58 mmol) and4-chlorophenoxyacetonitrile (10.7 g, 64 mmol) in DMF (50 ml) cooled at−15° C. was added potassium tert-butoxide (14.3 g, 127 mmol) in DMF (124ml). After stirring for 30 minutes at −15° C., the mixture was pouredonto cooled 1N hydrochloric acid. The mixture was extracted with ethylacetate. The organic layer was washed with 1N sodium hydroxide, brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride. The fractions containingthe expected product were combined and evaporated. The residue wasdissolved in ethanol (180 ml) and acetic acid (24 ml) containing 10%palladium on charcoal (600 mg) and the mixture was hydrogenated under 3atmospheres pressure for 2 hours. The mixture was filtered, and thevolatiles were removed under vacuum. The residue was partitioned betweenethyl acetate and water. The organic layer was separated, and washedwith saturated sodium hydrogen carbonate followed by brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography eluting with methylene chloride to give a mixture of4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole (5.64 g, 59%) in aratio 1/2.

¹H NMR Spectrum: (DMSOd₆) 3.85 (s, 3H); 6.38 (s, 1H, 6-Fluoro); 6.45 (s,1H; 4-Fluoro); 6.9–7.4 (m, 3H)

A solution of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole in aratio 1/2 (496 mg, 3 mmol), di-tertbutyl dicarbonate (720 mg, 3.3 mmol)in acetonitrile (12 ml) containing DMAP (18 mg, 0.15 mmol) was stirredat ambient temperature for 24 hours. The volatiles were removed undervacuum. The residue was dissolved in ethyl acetate, washed with 1Nhydrochloric acid, followed by water, brine, dried (MgSO₄) andevaporated to give a mixture of4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2 (702 mg,88%).

¹H NMR Spectrum: (DMSOd₆) 1.65 (s, 9H); 3.9 (s, 3H); 6.6 (d, 1H,6-fluoro); 6.72 (d, 1H, 4-fluoro); 7.2 (t, 1H, 6-fluoro); 7.4 (d, 1H,4-fluoro); 7.62 (d, 1H, 6-fluoro); 7.68 (d, 1H, 4-fluoro); 7.78 (s, 1H,4-fluoro); 7.85 (s, 1H, 6-fluoro)

To a solution of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2 (8.1 g,30.5 mmol) in THF (100 ml) cooled at −65° C. was added tert-butyllithium(1.7 M) (23 ml, 35.7 mmol). After stirring for 4 hours at −70° C.,methyl iodide (8.66 g, 61 mmol) was added and the mixture was left towarm-up to ambient temperature. Water was added and the mixture wasextracted with ether. The organic layer was washed with water, brine,dried (MgSO₄) and evaporated and was used directly in the next step.

The crude product was dissolved in methylene chloride (100 ml) and TFA(25 ml) was added. After stirring for 1 hour at ambient temperature, thevolatiles were removed under vacuum. The residue was dissolved in ethylacetate and the organic layer was washed with 1N sodium hydroxide,followed by water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography, eluting with ethyl acetate/petroleumether (3/7) to give 6-fluoro-5-methoxy-2-methylindole (1.6 g) and4-fluoro-5-methoxy-2-methylindole (0.8 g, 48%).

6-fluoro-5-methoxy-2-methylindole

MS-ESI: 180 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 3.8 (s, 3H); 6.05 (s, 1H); 7.1(s, 1H); 7.12 (s, 1H); 10.8 (s, 1H)

4-fluoro-5-methoxy-2-methylindole

MS-ESI: 180 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 3.8 (s, 3H); 6.15 (s, 1H); 6.9(t, 1H); 7.05 (d, 1H); 11.0 (s, 1H)

To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol)in methylene chloride (9 ml) cooled at −30° C. was added a solution ofboron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml). Afterstirring for 1 hour at ambient temperature, the mixture was poured ontowater and was diluted with methylene chloride. The pH of the aqueouslayer was adjusted to 6. The organic layer was separated, washed withwater, brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography, eluting with ethyl acetate/petroleum ether (3/7)to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70%).

MS-ESI: 166 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9(d, 1H); 8.75 (s, 1H); 10.9 (s, 1H)

¹³C NMR Spectrum: (DMSOd₆) 13.5; 94.0; 106.0; 112; 118.5 (d); 132 (d);136 (d) 136.5; 142.5 (d)

Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be prepared asfollows:

To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed withpentane) in THF (100 ml) cooled at 101C was added ethyl acetoacetate(29.4 g, 226 mmol) while keeping the temperature below 15C. Aftercompletion of addition, the mixture was further stirred for 15 minutesand cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g,113 mmol) in THF (150 ml) was added while keeping the temperature below5C. The mixture was then left to warm up to ambient temperature andstirred for 24 hours. The volatiles were removed under vacuum and theresidue was partitioned between ethyl acetate and 2N aqueoushydrochloric acid. The organic layer was washed with water, brine, dried(MgSO₄) and evaporated. The residue was dissolved in concentratedhydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture wasrefluxed for 15 hours. After cooling, the volatiles were removed undervacuum and the residue was partitioned between aqueous sodium hydrogencarbonate (5%) and ethyl acetate. The organic layer was washed withsodium hydrogen carbonate, water, brine, dried (MgSO₄) and evaporated.The residue was purified by column chromatography eluting withethylacetate/petroleum ether (75/25) to give3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).

¹H NMR Spectrum: (CDCl₃) 2.4 (s, 3H); 4.25 (s, 2H); 7.25 (dd, 1H); 8.0(dd, 1H)

A solution of 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (500 mg, 2.3mmol) in methylene chloride (5 ml) containing montmorillonite K10 (1 g)and trimethyl orthoformate (5 ml) was stirred for 24 hours at ambienttemperature. The solid was filtered, washed with methylene chloride andthe filtrate was evaporated to give1,2-difluoro-3-(2,2dimethoxypropyl)-4-nitrobenzene (534 mg, 88%).

¹H NMR Spectrum: (CDCl₃) 1.2 (s, 3H); 3.2 (s, 6H); 3.52 (s, 2H); 7.18(dd, 1H) 7.6 (m, 1H)

To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) wasadded 60% sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for1 hour at ambient temperature. A solution of1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol)in DMA (1.5 ml) was added and the mixture was stirred for 3 hours atambient temperature. The mixture was diluted with 1N hydrochloric acid(10 ml) and extracted with ethyl acetate. The organic layer wasevaporated and the residue was dissolved in THF (2 ml) and 6Nhydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hourat ambient temperature and the solvents were removed under vacuum. Theresidue was partitioned between ethyl acetate and water. The organiclayer was separated, washed with brine, dried (MgSO₄) and evaporated.The solid was triturated with ether, filtered, washed with ether anddried under vacuum to give3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56%).

¹H NMR Spectrum: (CDCl₃) 2.35 (s, 3H); 4.25 (s, 2H); 5.25 (s, 2H); 7.0(dd, 1H); 7.32–7.5 (m, 5H); 8.0 (dd, 1H)

A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10%palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressurefor 2 hours. The mixture was filtered and the filtrate was evaporated.The residue was dissolved in ethyl acetate and the organic layer waswashed with aqueous sodium hydrogen carbonate, brine and evaporated togive 4-fluoro-5-hydroxy-2-methylindole. The residue was purified bycolumn chromatography eluting with ethyl acetate/petroleum ether (3/7)to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%). Analytical dataas above.

Alternatively the 4-fluoro-5-methoxy-2-methylindole can be prepared asfollows:

A solution of sodium methoxide (freshly prepared from sodium (1.71 g)and methanol (35 ml)) was added to a solution of1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol),(prepared as described above), in methanol (200 ml) cooled at 5° C. Themixture was left to warm to ambient temperature and was stirred for 3days. The volatiles were removed under vacuum and the residue waspartitioned between ethyl acetate and 2N hydrochloric acid (1 ml). Theorganic layer was concentrated to a total volume of 100 ml and THF (100ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirredfor 1 hour at ambient temperature. The volatiles were removed undervacuum and the residue was partitioned between ethyl acetate and water.The organic layer was separated, washed with water, brine, dried (MgSO₄)and evaporated. The residue was purified by column chromatographyeluting with ethyl acetate/petroleum ether (3/7) to give3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%).

MS-ESI: 250 [MNa]+

¹H NMR Spectrum: (CDCl₃) 2.38 (s, 3H); 4.0 (s, 3H); 4.25 (s, 2H); 7.0(dd, 1H); 8.05 (d, 1H)

To a solution of 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (11.36g, 50 mmol) in acetone (200 ml) was added 4M aqueous ammonium acetate(700 ml) followed by a solution of titanium trichloride (15% in water,340 ml) dropwise. The mixture was stirred for 10 minutes at ambienttemperature and the mixture was extracted with ether. The organic layerwas washed with 0.5N aqueous sodium hydroxide followed by water, brine,dried (MgSO₄) and the volatiles were removed under vacuum. The residuewas purified by column chromatography eluting with methylene chloride togive 4-fluoro-5-methoxy-2-methylindole (8.15 g, 90%).

¹H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1 (s, 1H); 6.85(dd, 1H); 7.02 (d, 1H)

Cleavage of 4-fluoro-5-methoxy-2-methylindole with boron tribromide togive 4-fluoro-5-hydroxy-2-methylindole is described above.

EXAMPLE 238

Using an analogous procedure to that described in Example 237,4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.65 g, 4.89mmol), (prepared as described for the starting material in Example 67),was reacted with 4-fluoro-5-hydroxy-2-methylindole (970 mg, 5.88 mmol),(prepared as described for the starting material in Example 237), togive4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(1.9 g, 83%).

MS-ESI: 465 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.4 (br s, 2H); 1.5 (m, 4H); 1.95 (m, 2H);2.25–2.5 (m, 6H); 2.45 (s, 3H); 4.0 (s, 3H); 4.25 (t, 2H); 6.25 (s, 1H);7.0 (dd, 1H); 7.15 (d, 1H); 7.4 (s, 1H) 7.6 (s, 1H); 8.5 (s, 1H)

EXAMPLE 239

Using an analogous procedure to that described in Example 237,4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (106mg, 0.30 mmol), (prepared as described for the starting material inExample 176), was reacted with 4-fluoro-5-hydroxy-2methylindole (60 mg,0.36 mmol), (prepared as described for the starting material in Example237), to give4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(100 mg, 70%).

MS-ESI: 480 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.0 (t, 2H); 2.15 (s, 3H); 2.45 (s, 3H),2.2–2.6 (m, 10H); 4.02 (s, 3H); 4.25 (t, 2H); 6.25 (s, 1H); 7.0 (dd,1H); 7.18 (d, 1H); 7.4 (s, 1H); 7.62 (s, 1H); 8.5 (s, 1H)

EXAMPLE 240

Using a procedure identical to that described in Example 237,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (2 g, 6.22mmol), (prepared as described for the starting material in Example 9),was reacted with 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46 mmol),(prepared as described for the starting material in Example 237), togive4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(1.41 g, 50%).

MS-ESI: 451 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H); 2.0 (m, 2H); 2.41 (s, 3H); 2.5(br s, 4H); 2.6 (t, 2H);4.0 (s, 3H); 4.25 (t, 2H); 6.25 (s, 1H); 7.0(dd, 1H); 7.2 (d, 1H); 7.4 (s, 1H); 7.6 (s, 1H); 8.5 (s, 1H)

Elemental analysis: Found C 63.3 H 6.4 N 11.9 C₂₅H₂₇FN₄O₃ 1.08 H₂O;Requires C 63.6 H 6.3 N 11.8% 0.16 methanol

EXAMPLE 241

A solution of4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (300mg, 0.9 mmol) and 4-fluoro-5-hydroxyindole (162 mg, 1 mmol), (preparedas described for the starting material in Example 242), in DMF (4.5 ml)containing potassium carbonate (185 mg, 1.3 mmol) was stirred at 90° C.for 1 hour. After cooling, the mixture was filtered and the solid waswashed with DMF. The filtrate was evaporated and the residue waspurified by column chromatography, eluting with methylene chloridefollowed by methanol/methylene chloride (1/99) followed by methanolsaturated with ammonia/methylene chloride (2/98). The fractionscontaining the expected product were combined and evaporated. The solidwas triturated with ether, filtered, washed with ether and dried undervacuum to give4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline(282 mg, 69%).

MS-ESI: 451 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.2–1.3 (m, 2H); 1.4–1.55 (m, 1H); 1.7–1.9 (m,6H); 2.15 (s, 3H); 2.75 (d, 2H); 4.0 (s, 3H); 4.3 (t, 2H); 6.55 (s, 1H);7.1 (dd, 1H); 7.3 (d, 1H); 7.4 (s, 1H); 7.5 (s, 1H); 7.6 (s, 1H); 8.5(s, 1H); 11.5 (s, 1H)

The starting material was prepared as follows:

To a solution of 4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine(12.9 g, 56 mmol), (prepared as described for the starting material inExample 126), in tert-butyl methyl ether (120 ml) containing1,4-diazabicyclo[2.2.2]octane (9.8 g, 87 mmol) cooled at −5° C. wasadded a solution of tosyl chloride (14.5 gr, 76 mmol) in tert-butylmethyl ether (120 ml) dropwise whilst keeping the temperature below 0°C. After completion of addition, the mixture was left to warm up toambient temperature and stirred for 1 hour. The mixture was poured ontopetroleum ether (240 ml). The precipitae was filtered and washed withpetroleum ether. The filtrate was evaporated and the residue wasdissolved in ether. The ether layer was washed with 0.5 N hydrochloricacid, followed by saturated sodium hydrogen carbonate, dried (MgSO₄) andevaporated to give4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine(20.9 g, 97%).

¹H NMR Spectrum: (CDCl₃) 0.95–1.05 (m, 4H); 1.45 (s, 9H); 1.4–1.6 (m,3H)2.45 (s, 3H); 2.62 (t, 2H); 3.94.1 (m, 2H); 4.1 (t, 2H); 7.35 (d,2H); 7.8 (d, 2H)

A suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(7 g, 23 mmol), (prepared as described for the starting material inExample 12),4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine(11.4 g, 30 mmol) in DMF (70 ml) containing potassium carbonate (6.32 g,46 mmol) was stirred at 100° C. for 3 hours. After cooling, thevolatiles were removed under vacuum and the residue was partitionedbetween ether and water. The organic layer was separated, washed withwater, brine, dried (MgSO₄) and evaporated. The solid was trituratedwith pentane, filtered and dried under vacuum to give7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(10.5 g, 88%).

MS-ESI: 540 [MNa]⁺

¹H NMR Spectrum: (CDCl₃) 1.2 (s, 9H); 1.15–1.25 (m, 2H); 1.48 (s, 9H);1.65–1.75 (m, 1H) 1.7 (d, 2H); 1.9 (dd, 2H); 2.72 (t, 2H); 4.0 (s, 3H);4.04.2 (m, 2H); 4.2 (t, 2H); 5.95 (s, 2H); 7.1 (s, 1H); 7.65 (s, 1H);8.2 (s, 1H)

A solution of7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(10.5 g, 20 mmol) in methylene chloride (100 ml) containing TFA (25 ml)was stirred for 1 hour at ambient temperature. Water (50 ml) andmethylene chloride (100 ml) were added and the pH of the aqueous layerwas adjusted to 8 with solid sodium hydrogen carbonate. The organiclayer was separated, washed with water, brine, dried (MgSO₄) andevaporated. The residue was triturated with ether and the solid wasfiltered and dried under vacuum to give7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(8.3 g, 100%).

¹H NMR Spectrum: (CDCl₃) 1.2 (s, 9H); 1.65 (m, 2H); 1.9 (br s, 2H);1.8–1.9 (m, 1H); 2.0 (d, 2H); 2.9 (t, 2H); 3.45 (d, 2H); 4.0 (s, 3H);4.2 (t, 2H); 5.95 (s, 2H); 7.1 (s, 1H); 7.65 (s, 1H); 8.2 (s, 1H)

To a solution of7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(6 g, 14.4 mmol) in methanol (30 ml) and methylene chloride (60 ml) wasadded 37% aqueous formaldehyde (2.2 ml; 28.9 mmol) followed by aceticacid (990 μl; 17.3 mmol). Sodium borohydride triacetate (4.6 g, 21.6mmol) was added in portions. After stirring for 1 hour at ambienttemperature, the volatiles were removed under vacuum and the residue waspartitioned between water (50 ml) and methylene chloride (50 ml). The pHof the aqueous layer was adjusted to 7, washed with water, brine, dried(MgSO₄) and evaporated. The solid was triturated with ether, filtered,washed with ether and dried under vacuum to give7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(4.2 g, 68%).

MS-ESI: 432 [MH]⁺

¹H NMR Spectrum: (CDCl₃) 1.22 (s, 9H); 1.68 (br s, 3H); 1.9 (m, 4H);2.32 (br s, 2H); 2.52 (s, 3H); 3.18 (d, 2H); 4.0 (s, 3H); 4.2 (t, 2H);5.95 (s, 2H); 7.1 (s, 1H); 7.65 (s, 1H); 8.2 (s, 2H)

A solution of7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(4.2 g, 9.7 mmol) in methanol saturated with ammonia (150 ml) wasstirred overnight at ambient temperature. The volatiles were removedunder vacuum and the residue was triturated with ether. The solid wasfiltered, washed with ether and dried under vacuum to give7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(3.12 g, 100%).

MS-ESI: 318 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3 (m, 2H); 1.58 (br s, 1H); 1.72 (dd, 2H);1.8 (d, 2H); 2.4 (s, 3H); 2.2–2.45 (m, 2H); 3.0 (br s, 2H); 3.85 (s,3H); 4.15 (t, 2H); 7.15 (s, 1H); 7.45 (s, 1H); 8.0 (s, 1H)

A solution of7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(3.1 g, 9.8 mmol) in thionyl chloride (40 ml) containing DMF (400 μl)was refluxed for 4 hours. After cooling, the volatiles were removedunder vacuum. The residue was partitioned between methylene chloride andwater and the pH of the aqueous layer was adjusted to 11 with solidsodium hydrogen carbonate and aqueous ammonia. The organic layer wasseparated, dried (MgSO₄) and evaporated. The residue was triturated withether, filtered, washed with ether and dried under vacuum to give4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.83g, 54%).

MS-ESI: 336 [MH]⁺

¹H NMR Spectrum: (CDCl₃) 1.4–1.7 (m, 3H); 1.8 (d, 2H); 1.9 (dd, 2H);2.05 (t, 2H); 2.35 (s, 3H); 2.95 (d, 2H); 4.05 (s, 3H); 4.25 (t, 2H);7.3 (s, 1H); 7.4 (s, 1H); 8.88 (s, 1H)

EXAMPLE 242

A solution of4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (213mg, 0.662 mmol), (prepared as described for the starting material inExample 10), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol) in DMF (3ml) containing potassium carbonate (137 mg, 0.994 mmol) was stirred at95° C. for 3.5 hours. After cooling, the mixture was poured onto water.The mixture was filtered and the solid was washed with water. The solidwas dissolved in methylene chloride. The organic layer was dried(MgSO₄), and evaporated. The residue was triturated with ether/ethylacetate and the solid was filtered and dried under vacuum to give4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(135 mg, 46%).

MS-ESI: 437 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3–1.45 (m, 2H); 1.8 (d, 2H); 1.9 (t, 2H);1.7–1.9 (m, 1H); 2.17 (s, 3H); 2.8 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H);6.48 (br s, 1H); 7.38 (d, 1H); 7.4 (s, 1H); 7.42 (t, 1H); 7.58 (d, 1H);7.6 (s, 1H); 8.5 (s, 1H)

Elemental analysis Found C 65.0 H 5.8 N 12.7 C₂₄H₂₅FN₄O₃ 0.4 H₂ORequires C 65.0 H 5.9 N 12.6%

The starting material was prepared as follows:

A mixture of 2-fluoro-4-nitrophenol (15 gr, 95.5 mmol) and benzylbromide (18 g, 105 mmol) in acetone (125 ml) containing potassiumcarbonate (26.5 gr, 190 mmol) was refluxed for 2 hours. The volatileswere removed and the residue was partitioned between 2N hydrochloricacid and ethyl acetate. The organic layer was separated, washed withwater, brine, dried (MgSO₄) and the volatiles were removed under vacuum.The solid was triturated with petroleum ether to give2-fluoro-4-nitro-benzyloxybenzene (23 g, 97%).

¹H NMR Spectrum: (CDCl₃) 5.3 (s. 2H); 7.1 (t, 1H) 7.35–7.55 (m, 5H);8.0(m, 2H)

To a solution of potassium tert-butoxide (1.72 g, 15.4 mmol) in DMF (15ml) cooled at −30° C., was added dropwise a solution of2-fluoro-4-nitro-benzyloxybenzene (1.73 g, 7 mmol) and4-chlorophenoxyacetonitrile (1.29 g, 7.7 mmol) while maintaining thetemperature below −25° C. After completion of addition, the mixture wasstirred for 30 minutes at −20° C. and then poured onto a mixture of cold1N hydrochloric acid and ether. The organic layer was separated, washedwith 1N sodium hydroxide, followed by water, brine, dried (MgSO₄). Thevolatiles were removed under vacuum and the residue was purified bycolumn chromatography eluting with methylene chloride/petroleum ether(3/1) to give a mixture of3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (1.2 g, 60%).

¹H NMR Spectrum: (DMSOd₆) 4.22 (s, 2H, 3-cyanomethyl isomer); 4.3 (s,2H, 5cyanomethyl isomer); 5.32 (s, 2H, 5-cyanomethyl isomer); 5.36 (s,2H, 3-cyanomethyl isomer); 7.3–7.7 (m, 6H); 8.1 (d, 1H, 3-cyanomethylisomer); 8.2 (d, 1H, 5-cyanomethyl isomer)

A solution of a mixture of3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (23 g, 80.4 mmol) inethanol (220 ml) and acetic acid (30 ml) containing 10% palladium oncharcoal (600 mg) was hydrogenated under 3 atmospheres pressure untilhydrogen uptake ceased. The mixture was filtered and the filtrate wasevaporated under vacuum. The residue was purified on columnchromatography using a Prochrom® equipment eluting with methylenechloride/petroleum ether (20/80) to give 4-fluoro-5-hydroxyindole (2.48g) and 6-fluoro-5-hydroxyindole (3.5 g).

4-fluoro-5-hydroxyindole

¹H NMR Spectrum: (DMSOd₆) 6.32 (s, 1H); 6.75 (dd, I H); 7.0 (d, 1H);7.28 (dd, 1H); 8.8 (br s, 1H); 11.05 (br s, 1H)

6-fluoro-5-hydroxyindole

¹H NMR Spectrum: (DMSOd₆) 6.25 (s, 1H); 7.0 (d, 1H); 7.12 (d, 1H); 7.2(dd, I H); 9.0 (br s, 1H)

EXAMPLE 243

A solution of4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (213mg, 0.662 mmol), (prepared as described for the starting material inExample 10), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),(prepared as described for the starting material in Example 242), in DMF(3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was stirredat 95° C. for 3 hours. After cooling, the mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withwater, brine, dried (MgSO₄) and evaporated. The residue was trituratedin cold ether. The solid was filtered and dried under vacuum to give4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(77 mg, 26%).

MS-ESI: 437 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.8 (d, 2H); 1.9 (t, 2H);1.7–1.95 (m, 1H); 2.2 (s, 3H); 2.8 (d, 2H); 4.02 (s, 3H); 4.1 (d, 2H);6.55 (s, 1H); 7.1 (t, 1H); 7.3 (d, 1H) 7.4 (s, 1H); 7.48 (t, 1H); 7.62(s, 1H); 8.5 (s, 1H)

Elemental analysis Found C 64.8 H 5.8 N 12.6 C₂₄H₂₅FN₄O₃ 0.4 H₂ORequires C 65.0 H 5.9 N 12.6%

EXAMPLE 244

A mixture of4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (282mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),(prepared as described for the starting material in Example 242), in DMF(3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was heated at95° C. for 3 hours. After cooling, the residue was poured in water (12ml) and the pH was adjusted to 8. The mixture was extracted with ethylacetate. The organic layer was separated, washed with water, brine,dried (MgSO₄) and evaporated. The residue was purified by preparativecolumn chromatography on C¹⁸ silica eluting with 60% methanol in aqueousammonium carbonate (2 g ammonium carbonate/liter saturated with CO₂).The fractions containing the expected product were combined andevaporated. The residue was triturated with ether and the solid wasfiltered, dried under vacuum to give4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(147 mg, 48%).

MS-ESI: 466 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.3–2.4 (m, 2H); 3.0 (s, 3H); 3.2–3.9(m, 8H); 3.5 (t, 2H); 4.1 (s, 3H); 4.4 (t, 2H); 6.52 (d, 1H); 7.45 (d,1H); 7.48 (s, 1H); 7.6 (s, 1H) 7.65 (d, 1H); 7.82 (s, 1H); 9.0 (s, 1H)

Elemental analysis Found C 62.1 H 6.4 N 14.2 C₂₅H₂₈FN₅O₃ 0.9 H₂ORequires C 62.3 H 6.2 N 14.5%

The starting material was prepared as follows:

To a suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(29 g, 94.7 mmol), (prepared as described for the starting material inExample 12), in methylene chloride (280 ml) colled at 5° C. was addedtriphenylphosphine (37.1 g, 141.6 mmol) followed by 3-bromo-1-propanol(12.8 ml, 141.6 mmol) and diethyl azodicarboxylate (2.4 ml, 141.6 mmol)dropwise. After stirring for 2 hours at ambient temperature, thevolatiles were removed under vacuum and the residue was purified bycolumn chromatography eluting with methylene chloride/methanol (98/2).The fractions containing the expected product were combined andevaporated and the solid was triturated with ether, filtered, washedwith ether and dried under vacuum to give7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(37.22 g, 92%).

MS-ESI: 427–429 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.18 (s, 9H); 2.32 (m, 2H); 3.7 (t, 2H); 3.92(s, 3H); 4.28 (t, 2H); 5.95 (s, 2H); 7.2 (s, 1H); 7.5 (s, 1H); 8.4 (s,1H)

A suspension of7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(36.7 g, 86 mmol) in 1-methylpiperazine (370 ml) was stirred at 100° C.for 90 minutes. After removal of the volatiles under vacuum, the residuewas partitioned between methylene chloride and aqueous ammoniumchloride. The organic layer was separated, washed with water, brine,dried (MgSO₄) and evaporated. The solid was triturated with ether,filtered, washed with ether and dried under vacuum to give7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(31.9 gr, 83%).

MS-ESI: 447 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.15 (s, 9H); 2.25 (t, 2H); 2.5 (s,3H); 3.45 (t, 2H); 3.24.0 (m, 8H); 3.9 (s, 3H); 4.25 (t, 2H); 5.95 (s,2H); 7.22 (s, 1H); 7.55 (s, 1H); 8.6 (s, 1H)

A suspension of7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(31.8 g, 71.3 mmol) in methanol saturated with ammonia was stirred atambient temperature overnight. The volatiles were removed under vacuum.The solid was triturated with ether containing about 10% of methylenechloride, filtered, washed with ether containing about 10% methylenechloride and dried under vacuum to give7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(22.63 g, 95%).

MS-ESI: 333 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.92 (m, 2H); 2.15 (s, 3H); 2.2–2.5 (m, 10H);3.88 (s, 3H) 4.15 (t, 2H); 7.1 (s, 1H); 7.45 (s, 1H); 7.98 (s, 1H)

A solution of7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(22.6 g, 68 mmol) in thionyl chloride (300 ml) cotaining DMF (5 ml) wasrefluxed for 2 hours. After cooling, the volatiles were removed undervacuum and the residue was azeotroped with toluene twice. The solid wasdissolved in methulene chloride and water was added. The mixture wascooled to 0° C. and the pH of the aqueous layer was adjusted to 7 withsolid hydrogen carbonate and then raised to 10 with 6N Sodium hydroxide.The organic layer was separated and the aqueous layer was extracted withmethylene chloride. The organic layer was washed with brine, dried(MgSO₄), filtered and the volatiles were removed under vacuum. Theresidue was triturated with ether, filtered, washed with ether and driedunder vacuum to give4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(16.3 gr, 68%).

MS-ESI: 351–353 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.98 (t, 2H); 2.18 (s, 3H); 2.45 (t, 2H);2.22–2.5 (m, 8H); 4.05 (s, 3H); 4.28 (t, 2H); 7.4 (s, 3H); 7.45 (s, 1H);8.9 (s, 1H)

EXAMPLE 245

Using an analogous procedure to that described in Example 243,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (213 mg,0.662 mmol), (prepared as described for the starting material in Example9), was reacted with 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),(prepared as described for the starting material in Example 242), in DMF(3 ml) containing potassium carbonate (137 mg, 0.993 mmol) to give4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(154 mg, 53%).

MS-ESI: 437 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.7–1.8 (m, 4H); 2.0–2.1 (m, 2H); 2.48 (br s,4H); 2.6 (t, 2H); 4.02 (s, 3H); 4.3 (t, 2H); 6.5 (s, 1H); 7.4 (d, 1H);7.4 (s, 1H); 7.45 (t, 1H); 7.6 (d, 1H); 7.62 (s, 1H); 8.52 (s, 1H)

Elemental analysis Found C 65.4 H 6.0 N 12.9 C₂₄H₂₅HN₄O₃ 0.2 H₂ORequires C 65.5 H 5.8 N 12.7%

EXAMPLE 246

To a solution of6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(500 mg, 1.2 mmol), (prepared as described in example 70), in methanol(11.5 ml) containing potassium iodide (99 mg, 0.6 mmol) was added4-(2chloroethyl)morpholine hydrochloride (134 mg, 0.72 mmol) followed bysodium hydrogen carbonate (151 mg, 1.8 mmol). After stirring for 1 hourat reflux, 4-(2-chloroethyl)morpholine hydrochloride (134 mg, 0.72 mmol)and sodium hydrogen carbonate (151 mg, 1.8 mmol) were added. Afterstirring 1 hour at reflux, the mixture was cooled and the precipitatewas filtered, washed with methanol followed by water and dried overphosphorus pentoxide to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline(470 mg, 73%).

MS-ESI: 532 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3–1.45 (m, 2H); 1.8 (d. 2H); 1.7–1.9 (m,1H); 2.0 (t, 2H); 2.3–2.45 (m, 8H); 2.4 (s, 3H); 2.95 (d, 2H); 3.6 (t,4H) 4.0 (s, 3H); 4.08 (d, 2H); 6.18 (s, 1H); 6.9(dd, 1H);7.3 (s, 1H);7.35(d, 1H); 7.4(s, 1H); 7.6(s, 1H); 8.5(s, 1H); 11.05(s, 1H)

Elemental analysis Found C 65.3 H 7.1 N 12.6 C₃₀H₃₇N₅O₄ 0.6 H₂O RequiresC 65.4 H 7.3 N 12.5% 0.6 Methanol

EXAMPLE 247

A solution of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.76 g,5.47 mmol), (prepared as described for the starting material in Example9), 4-fluoro-5-hydroxyindole (0.992 g, 6.57 mmol), (prepared asdescribed for the starting material in Example 242), in DMF (25 ml)containing potassium carbonate (1.14 g; 8.21 mmol) was heated at 95° C.for 1 hour. After cooling, the mixture was filtered and washed with DMF.The filtrate was evaporated and the residue was purified by columnchromatography eluting with methanol/methylene chloride (1/9) followedby methanol/methanol chloride/methanol (containing ammonia) (16/80/4).The fractions containing the expected product were combined andevaporated. The residue was repurified by column chromatography elutingwith a gradient of methylene chloride/methanol (80/20 to 40/60). Thefractions containing the expected product were combined and evaporated.The residue was triturated in cold methanol and the solid was filtered,washed with ether and dried under vacuum to give4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(1.24 g, 52%).

MS-ESI: 437 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H); 2.0 (m, 2H); 2.45 (br s, 4H);2.6 (t, 2H); 4.05 (s, 3H); 4.28 (t, 2H); 6.58 (s, 1H); 7.1 (t, 2H); 7.35(d, 1H); 7.4 (s, 1H); 7.5 (t, 1H) 7.65 (s, 1H); 8.52 (s, 1H)

Elemental analysis Found C 65.3 H 5.9 N 12.6 C₂₄H₂₅FN₄O₃ 0.19 Methanol,Requires C 65.2 H 5.9 N 12.6% 0.17 H₂O

EXAMPLE 248

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (222mg, 0.662 mmol), (prepared as described for the starting material inExample 67), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),(prepared as described for the starting material in Example 242), in DMF(3 ml) containing potassium carbonate (137 mg, 0.993 mmol) was heated at95° C. for 3.5 hours. After cooling the mixture was poured onto waterand extracted with ethyl acetate. The organic layers were washed withwater, brine, dried (MgSO₄) and evaporated. The residue was trituratedwith ether, filtered and dried under vacuum to give4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(139 mg, 46%).

MS-ESI: 451 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H); 1.45–1.6 (m, 4H); 2.0 (m,2H); 2.35 (br s, 4H); 2.42 (t, 2H); 4.05 (s, 3H); 4.25 (t, 2H); 6.5 (s,1H); 7.4 (d, 1H); 7.42 (s, 1H); 7.44 (t, 1H); 7.6 (d, 1H); 7.65 (s, 1H);8.5 (s, 1H)

Elemental analysis Found C 65.9 H 6.2 N 12.3 C₂₅H₂₇FN₄O₃ 0.3 H₂ORequires C 65.9 H 6.1 N 12.3%

EXAMPLE 249

Using an analogous procedure to that described in Example 244,4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (407 mg, 1.21mmol), (prepared as described for the starting material in Example 67),4-fluoro-5-hydroxyindole (220 mg, 1.45 mmol) (prepared as described forthe starting material in Example 242), and potassium carbonate (251 mg,1.82 mmol) in DMF (6 ml) were heated at 95° C. for 90 minutes andpurified to give4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(367 mg, 67%).

MS-ESI: 451 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.35–1.45 (m, 2H); 1.55 (m, 4H); 2.0 (m, 2H);2.38 (br s, 4H); 2.45 (t, 2H); 4.02 (s, 3H); 4.25 (t, 2H); 6.55 (s, 1H);7.12 (dd, 1H); 7.32 (d, 1H); 7.4 (s, 1H); 7.5 (s, 1H); 7.65 (s, 1H);8.52 (s, 1H)

Elemental analysis Found C 66.0 H 6.2 N 12.4 C₂₅H₂₇FN₄O₃ 0.2 H₂ORequires C 66.1 H 6.1 N 12.3%

EXAMPLE 250

Using an analogous procedure to that described in Example 248,4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (268 mg,0.833 mmol), (prepared as described for the starting material in Example9), was reacted with 6-fluoro-5-hydroxy-2-methylindole (165 mg, 1 mmol)in DMF (3.5 ml) containing potassium carbonate (173 mg, 1.25 mmol) togive4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(215 mg, 57%).

MS-ESI: 451 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.65–1.8 (br s, 4H); 2.02 (m, 2H); 2.4 (s,3H); 2.48 (br s, 4H); 2.6 (t, 2H); 4.02 (s, 3H); 4.3 (t, 2H); 6.18 (s,1H); 7.25 (d, 1H); 7.4 (s, 1H); 7.45 (d, 1H); 7.6 (s, 1H); 8.5 (s, 1H)

Elemental analysis Found C 65.6 H 6.1 N 12.2 C₂₅H₂₇FN₄O₃ 0.4 H₂ORequires C 65.6 H 6.1 N 12.2%

The starting material was prepared as follows:

To a solution of 6-fluoro-5-methoxy-2-methylindole (1.23 g, 6.86 mmol),(prepared as described for the starting material in Example 237), inmethylene chloride (15 ml) cooled at −30° C. was added a solution ofboron tribromide (3.78 g, 15.1 mmol) in methylene chloride (2 ml). Afterstirring for 90 minutes at ambient temperature, the mixture was pouredonto ice and diluted with methylene chloride. The pH of the aqueouslayer was adjusted to 6. The organic layer was separated, washed withwater, brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography eluting with ethylacetate/petroleum ether (8/2) togive 6-fluoro-5-hydroxy-2-methylindole (905 mg, 80%).

MS-ESI: 166 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.3 (s, 3H); 5.95 (s, 1H); 6.9 (d, 1H); 7.0(d, 1H); 8.85 (s, 1H); 10.6(s, 1H)

¹³C NMR Spectrum: (DMSOd₆) 13.3; 97.4 (d); 98.3; 105.5; 124.5; 128.8(d); 135.6; 138.5 (d); 148.3 (d).

EXAMPLE 251

A mixture of4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (232mg, 0.662 mmol), (prepared as described for the starting material inExamples 176 or 244), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),(prepared as described for the starting material in Example 242), in DMF(3 ml) containing potassium carbonate (137 mg, I mmol) was stirred at95° C. for 3 hours. After cooling, the residue was poured onto water (12ml) and extracted with ethyl acetate. The organic layer was washed withwater, brine, dried (MgSO₄) and evaporated. The residue was purified byreversed phase C₁₈ column chromatography eluting with methanol/ammoniumcarbonate (2 g of ammonium carbonate/liter saturated with CO₂) (60/40followed by 70/30). The fractions containing the expected product werecombined and evaporated. The residue was dissolved in ethyl acetate,dried (MgSO₄) and the volatiles were removed under vacuum. The residuewas triturated with ether, filtered and dried under vacuum to give4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline(130 mg, 42%).

MS-ESI: 466 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.3–2.4 (m, 2H); 2.97 (s, 3H);3.2–4.1 (m, 8H); 3.5 (t, 2H);4.07 (s, 3H);4.4 (t, 2H); 6.6 (d, 1H); 7.15(t, 1H); 7.38 (d, 1H); 7.5 (d, 1H); 7.6 (s, 1H); 7.82 (s, 1H); 8.95 (s,1H).

Elemental analysis Found C 64.4 H 6.1 N 15.0 C₂₅H₂₈FN₅O₃ Requires C 64.5H 6.1 N 15.0%

EXAMPLE 252

A mixture of6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(600 mg, 1.43 mmol), (prepared as described in Example 70),1-(2-chloroethyl)-pyrrolidine (292 mg, 1.72 mmol) in methanol (14 ml)containing sodium carbonate (262 mg, 4.3 mmol) and potassium iodide (48mg, 0.29 mmol) was heated at 50° C. for 20 hours. After cooling, thevolatiles were removed under vacuum. The residue was purified bypreparation HPLC on reverse C₁₈ silica eluting with methanol/aqueousammonium carbonate (2 g ammonium carbonate per liter saturated with CO₂)(60/40 followed by 70/30). The fractions containing the expected productwere combined and the volatiles were removed under vacuum. The residuewas triturated with ether and the solid was filtered, washed with etherand dried under vacuum to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline(102 mg, 20%).

MS-ESI: 516 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.3–1.5 (m, 2H); 1.6–1.75 (m, 4H); 1.8 (d,2H); 1.7–1.9 (m, 1H); 1.95 (t, 2H); 2.45 (s, 3H); 2.4–2.5 (m, 5H); 2.95(d, 2H); 3.35 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H); 6.18 (s, 1H); 6.9 (d,1H); 7.25 (s, 1H); 7.35 (d, 1H); 7.38 (s, 1H); 7.6 (s, 1H); 8.5 (s, 1H);11.05 (s, 1H)

Elemental analysis Found C 68.6 H 7.2 N 13.3 C₃₀H₃₇N₅O₃ 0.5 H₂O RequiresC 68.7 H 7.3 N 13.4%

EXAMPLE 253

A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110mg, 0.325 mmol), (prepared as described for the starting material inExample 1), and 6-fluoro-5-hydroxyindole (59 mg, 0.39 mmol), (preparedas described for the starting material in Example 242), in DMF (1.8 ml)containing potassium carbonate (67 mg, 0.487 mmol) was heated at 90° C.for 2 hours. After cooling, water was added. The solid was separated andtriturated with methanol. Water was added and the solid was filtered,washed with water and dried under vacuum to give4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline(55 mg, 41%).

MS-ESI: 453 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.95–2.05 (m, 2H); 2.45 (br s, 4H); 2.5 (t,2H); 3.62 (t, 4H); 4.02 (s, 3H); 4.3 (t, 2H); 6.5 (s, 1H); 7.4 (d, 1H);7.45 (s, 1H); 7.47 (t, 1H); 7.58 (d, 1H) 7.62 (s, 1H); 8.5 (s, 1H)

Elemental analysis Found C 61.6 H 5.5 N 11.9 C₂₄H₂₅FN₄O₄ 0.8 H₂ORequires C 61.7 H 5.7 N 12.0%

EXAMPLE 254

To a solution of 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183mg, 0.6 mmol), (prepared as described for the starting material inExample 107), triphenylphosphine (235 mg, 0.89 mmol) and4-(2-hydroxyethyl)morpholine (93 mg, 0.72 mmol) in methylene chloride (4ml) cooled at 10° C. was added diethyl azodicarboxylate (140 μl, 0.89mmol). After stirring at ambient temperature for 3 hours, the mixturewas left overnight at 5° C. The mixture was poured onto a column ofsilica and eluted with methylene chloride followed by methanol/methylenechloride (2/98) followed by 3N ammonia methanol/methylene chloride(2/98). The fractions containing the expected products were combined andevaporated to give4-(indol-5-yloxy)6-methoxy-7-(2-morpholinoethoxy)quinazoline (137 mg,55%).

MS-ESI: 421 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 3.30 (t, 2H); 3.65 (d, 2H); 3.7–3.8(m, 4H); 4.05 (d, 2H); 4.1 (s, 3H); 4.7 (t, 2H); 6.5 (s, 1H); 7.05 (dd,1H); 7.4–7.6 (m, 3H); 7.65 (s, 1H) 7.82 (s, 1H) 9.0 (s, 1H)

EXAMPLES 255–257

Using an analogous procedure to that described in Example 254,7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol),(prepared as described for the starting material in Example 107), wasused to prepare the compounds in Table XVIII.

TABLE XVIII

Example Weight number (mg) Yield % MS-ESI [MH]⁺ R Note 255 123 51 405

a 256 124 48 434

b 257 165 62 448

c a 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol)was reacted with 1-(2-hydroxyethyl)pyrrolidine (82 mg) to give4-(indol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline. ¹HNMR Spectrum: (DMSOd₆) 1.72(br s, 4H); 2.6(br s, 4H); 2.9(t, 2H); 4.0(s,3H); 4.3(t, 2H); 6.48(s, 1H); 7.0(dd, 1H); 7.4–7.5(m, 3H); 7.6(s, 1H);8.5(s, 1H); 11.3(br s, 1H) b7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol) wasreacted with 4-(2-hydroxyethyl)-1-methylpiperazine (103 mg) to give4-(indol-5-yloxy)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.5(s, 3H); 3.35(t, 2H); 3.65(d, 2H);3.7–3.8(m, 4H); 4.05(d, 2H); 4.1(s, 3H); 4.7(t, 2H); 7.05(dd, 1H);7.45(s, 1H); 7.5–7.6(m, 2H); 7.65(s, 1H); 7.82(s, 1H); 9.0(s, 1H) Thestarting material was prepared as follows:- 2-Bromoethanol (2.36 g, 19mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150ml) and the mixture heated at reflux for 18 hours. The mixture wasallowed to cool and the precipitates were removed by filtration and thesolvent volatiles were removed by evaporation. The residue was treatedwith acetone/methylene chloride, the insolubles were removed byfiltration and the solvent was removed from the filtrate by evaporationto give 4-(2-hydroxyethyl)-1-methylpiperazine (870 mg, 48%) as a lightbrown oil. ¹H NMR Spectrum: (CDCl₃) 2.18(s, 3H); 2.3–2.7(br m, 8H);2.56(t, 2H); 3.61(t, 2H) MS-ESI: 145 [MH]⁺ c7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol) wasreacted with 1-(3-hydroxypropyl)-4-methylpiperazine (113 mg), (preparedas described for the starting material in Example 133), to give4-(indol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline.¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H); 2.3–2.4(br s, 4H); 2.5–2.6(m,4H); 2.8(t, 2H); 4.0(s, 3H); 4.35(t, 2H); 6.45(s, 1H); 7.0(dd, 1H);7.4–7.5(m, 4H); 7.62(s, 1H); 8.5(s, 1H)

EXAMPLE 258

A solution of(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline(570 mg, 1.12 mmol) in methanol saturated with ammonia (7 ml) wasstirred overnight at ambient temperature. The volatiles were removedunder vacuum and the residue was purified by column chromatographyeluting with methylene chloride/methanol containing ammonia(approximately 3N) to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline(390 mg; 75%).

MS-ESI: 467 [MH]+

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.85–2.0 (m, 2H); 2.0–2.15 (m, 2H);2.42 (s, 3H); 3.15 (m, 2H); 3.4 (d, 2H); 3.65 (m, 2H); 4.1(s, 3H); 4.32(d, 2H); 4.4 (m, 1H); 7.05 (dd, 1H); 7.22 (d, 1H); 7.6 (s, 1H); 7.85 (s,1H); 9.02 (s, 1H)

The starting material was prepared as follows:

A suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.2 g, 3.91 mmol), (prepared as described for the starting material inExample 12), and 2-(R)-(−)-Glycidyl tosylate (1.25 g, 5.47 mmol) in DMF(10 ml) containing potassium carbonate (1.61 g, 11.7 mmol) was stirredat 60° C. for 4 hours. After cooling, the mixture was filtered and thesolid was washed with DMA. The filtrate was evaporated and the residuewas partitioned between ethyl acetate and aqueous ammonia. The organiclayer was separated, washed with water, brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography elutingwith ethyl acetate. The fractions containing the expected product werecombined and evaporated to give(2R)-7-(oxiran-2-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.21 g, 85%).

MS-ESI: 363 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 1.12 (s, 9H); 2.75 (m, 1H); 2.9 (t, 1H); 3.4(m, 1H); 3.93 (s, 3H); 4.0 (dd, 11H); 4.52 (dd, 1H); 5.9 (s, 2H); 7.2(s, 1H); 7.52 (s, 1H); 8.35 (s, 1H)

A solution of(2R)-7-(oxiran-2-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(1.1 g, 3 mmol) and pyrrolidine (216 mg, 3 mmol) in trichloromethane (15ml) was refluxed for 11 hours. The volatiles were removed under vacuumand the residue was purified by column chromatography eluting withmethylene chloride/methanol (85/15 followed by 70/30) to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one(118 g, 90%).

¹H NMR Spectrum: (DMSOd₆) 1.15 (s, 9H); 1.7 (br s, 4H); 2.48 (m, 1H);2.5 (br s, 4H); 2.65 (dd, 1H); 3.9 (s, 3H); 4.0 (br s, 1H); 4.05 (dd,1H); 4.18 (dd, 1H); 4.95 (br s, 1H); 5.9 (s, 2H); 7.2 (s, 1H); 7.5 (s,1H); 8.35 (s, 1H)

A solution of(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one(778 mg, 1.8 mmol) in methanol saturated with ammonia (20 ml) wasstirred for 24 hours at ambient temperature. The volatiles were removedunder vacuum. The residue was triturated with ether and the residue wasfiltered, washed with ether and dried under vacuum to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(800 mg, quant.).

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.92 (m, 2H); 2.05 (m, 2H); 3.15 (m,2H); 3.35 (d, 2H); 3.62 (m, 2H); 3.98 (s, 3H); 4.18 (d, 2H); 4.32 (m,1H); 7.35 (s, 1H);7.6 (s, 1H); 9.2 (s, 1H)

A mixture of(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(803 mg, 2.51 mmol) in acetic anhydride (1.2 ml, 12.5 mmol) was stirredat ambient temperature for 1 hour. Water (360 μl, 20 mmol) was added andstirring was continued for 90 minutes. The mixture was partitionedbetween aqueous sodium hydrogen carbonate and methylene chloride. Theorganic layer was separated, washed with brine, dried (MgSO₄) andevaporated. The residue was triturated with ether, filtered and driedunder vacuum to give(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(595 mg, 65%).

MS-ESI: 362 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H); 2.05 (s, 3H); 2.5 (br s, 4H);2.72 (m, 2H); 3.9 (s, 3H); 4.3 (m, 2H); 5.25 (m, 1H); 7.2 (s, 1H); 7.45(s, 1H); 8.0 (s, 1H)

A solution of(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one(556 mg, 1.54 mmol) in thionyl chloride (6 ml) containing DMF (3 drops)was heated at 80° C. for 4 hours. The volatiles were removed undervacuum. The residue was dissolved in methylene chloride and the organiclayer was washed with aqueous sodium hydrogen carbonate, brine, dried(MgSO₄) and evaporated to give(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline(530 mg, 90%).

¹H NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H); 2.05 (s, 3H); 2.55 (br s, 4H);2.75 (br s, 2H); 4.02 (s, 3H); 4.35–4.5 (m, 2H); 5.3 (m, 1H); 7.4 (s,1H); 7.5 (s, 1H); 7.9 (s, 1H)

A suspension of(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)4-chloro-6-methoxyquinazoline(530 mg, 1.4 mmol) and 4-fluoro-5-hydroxy-2-methylindole (277 mg, 1.68mmol), (prepared as described for the starting material in Example 237),in DMF (8 ml) containing potassium carbonate (290 mg, 2.1 mmol) wasstirred at 90° C. for 2 hours. After cooling, the volatiles were removedunder vacuum and the residue was purified by column chromatographyeluting with methylene chloride/methanol (95/5) to give(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline(580 mg, 81%).

¹H NMR Spectrum: (DMSOd₆) 1.7 (br s, 4H); 2.05 (s, 3H); 2.4 (s, 3H);2.52 (br s, 4H); 2.65–2.82 (m, 2H); 4.0 (s, 3H); 4.4 (m, 2H); 5.3 (m,1H); 6.25 (s, 1H); 7.0 (dd, 1H); 7.18 (d, 1H); 7.48 (s, 1H); 7.62 (s,1H); 8.5 (s, 1H)

EXAMPLE 259

A solution of4-chloro-6-methoxy-7(3-(pyrrolidin-1-yl)propoxy)quinazoline (61 mg, 0.19mmol), (prepared as described for the starting material in Example 9),and 5-aminoindole (30 mg, 0.23 mmol) in isopropanol (2 ml) containing6.2 N hydrogen chloride in isopropanol (33 μl) was heated at 80° C. for6 hours. After cooling, the precipitate was filtered, washed with etherand dried under vacuum to give4-(indol-5-ylamino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolinehydrochloride (80 mg, 72%).

MS-ESI: 418 [MH]⁺

¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 1.9 (m, 2H); 2.05 (m, 2H); 2.3 (m,2H); 3.1 (m, 2H); 3.4 (t, 2H); 3.65 (In, 2H); 4.05 (s, 3H); 4.35 (t,2H); 6.5 (s, 0.5H, partly exchanged); 7.3 (d, 1H); 7.4 (s, 1H); 7.45 (s,1H); 7.55 (d, 1H); 7.8 (s, 1H); 8.25 (s, 1H); 8.8 (s, 1H)

EXAMPLE 260–265

Using an analogous procedure to that described in Example 259,5-aminoindole (30 mg, 0.23 mmol) was used in the synthesis of thecompounds described in Table XIX.

TABLE XIX

Example Weight Yield MS-ESI number (mg) (%) [MH]⁺ Note R 260 101 76 510a

261 92 83 418 b

262 92 80 434 c

263 84 80 427 d

264 78 79 401 e

265 72 70 416 f

a4-Chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline(78 mg), (prepared as described for the starting material in Example12), was reacted with 5-aminoindole to give4-(indol-5-ylamino)-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆) 1.65–1.8(m, 2H); 2.05(d, 2H);2.2(br s, 1H); 3.1(br s, 2H); 3.2(s, 3H); 3.5(br s, 2H); 3.6(d, 2H);3.8(m, 2H); 4.05(s, 3H); 4.1(d, 2H); 6.5(s, 1H); 7.3(d, 1H); 7.42(m,2H); 7.5(d, 1H); 7.8(s, 1H); 8.4(s, 1H); 8.7(s, 1H); 11.15(br s, 1H);11.32(s, 1H). 11.5(s, 1H). b4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (61mg), (prepared as described for the starting material in Example 10),was reacted with 5-aminoindole to give4-(indol-5-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆) 1.6–1.8(m, 2H); 2.02(d, 2H);2.15(br s, 1H); 2.75(s, 3H); 3.0(br s, 2H); 3.45(d, 2H); 4.02(s, 3H);4.1(d, 2H); 6.5(s, 1H); 7.3(d, 1H); 7.4(m, 2H); 7.5(d, 1H); 7.8(s, 1H);8.3(s, 1H); 8.7(s, 1H); 10.4(br s, 1H); 11.3(s, 1H) The presence of asecond form of the piperidine ring (due to protonation effects) isdetectable in the NMR Spectrum as a doublet at 4.3 ppm (approximately20% of parent compound). c4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (64 mg), (preparedas described for the starting material in Example 1), was reacted with5-aminoindole to give4-(indol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazolinehydrochloride. ¹H NMR Spectrum (DMSOd₆; CF₃COOD): 2.35(m, 2H); 3.15(t,2H); 3.3(t, 2H); 3.57(d, 2H); 3.8(m, 2H); 4.02(d, 2H); 4.03(s, 3H);4.3(t, 2H); 6.5(d, 1H); 7.3(dd, 1H); 7.4(s, 1H); 7.45(s, 1H); 7.52(d,1H); 7.8(s, 1H); 8.25(s, 1H); 8.78(s, 1H) d4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (62 mg);(prepared as described for the starting material in Example 50), wasreacted with 5-aminoindole in the presence of 6.2N hydrogen chloride inisopropanol (4 μl) to give4-(indol-5-ylamino)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.2–2.4(m, 2H);3.07(s, 3H); 3.35(t, 2H); 4.05(s, 3H); 4.35(t, 2H); 6.5(d, 0.5H, partlyexchanged); 7.2–7.35(m, 2H); 7.45(s, 1H); 7.5(d, 1H); 7.8(s, 1H); 8.2(s,1H); 8.75(s, 1H) e4-Chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (58 mg) wasreacted with 5-aminoindole in the presence of 6.2N hydrogen chloride inisopropanol (4 μl) to give4-(indol-5-ylamino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 4.03(s, 3H); 4.65(t,2H); 4.8(t, 2H); 6.5(d, 1H, partly exchanged); 7.30(d, 1H); 7.4(s, 1H);7.45(s, 1H); 7.52(d, 1H); 7.75(s, 1H); 7.8(s, 1H); 7.9(s, 1H); 8.25(s,1H); 8.75(s, 1H); 9.25(s, 1H) The starting material was prepared asfollows: Diethyl azodicarboxylate (435 mg, 2.5 mmol) was added dropwiseto a suspension of7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(612 mg, 2 mmol), (prepared as described for the starting material inExample 12), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J. Med. Chem.1993, 25 4052–4060), and triphenylphosphine (655 mg, 2.5 mmol) inmethylene chloride (10 ml) at 5° C. The mixture was stirred for 10minutes at 5° C. and then 1 hour at ambient temperature. The mixture waspoured directly on to a silica column and eluted with methylenechloride/methanol (95/5) to give7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(640 mg, 80%). ¹H NMR Spectrum: (CDCl₃) 1.19(s, 9H); 3.98(s, 3H);4.34(m, 2H); 4.45(m, 2H); 5.94(s, 2H); 7.02(s, 1H); 7.07(s, 1H); 7.11(s,1H); 7.64(s, 1H); 7.67(s, 1H); 8.17(s, 1H) MS-ESI: 423 [MNa]⁺ ElementalAnalysis: Found C 58.3 H 6.4 N 13.9 C₂₀H₂₄N₄O₅ 0.7H₂O Requires C 58.2 H6.2 N 13.6% A solution of7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one(640 mg, 1.6 mmol) in saturated methanolic ammonia (10 ml) was stirredfor 15 hours at ambient temperature. The volatiles were removed byevaporation, the solid was triturated with ether, collected byfiltration and dried under vacuum to give7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 90%). ¹H NMR Spectrum: (DMSOd₆) 3.89(s, 3H); 4.4–4.5(m, 4H); 6.9(s,1H); 7.16(s, 1H); 7.28(s, 1H); 7.47(s, 1H); 7.7(s, 1H); 7.99(s, 1H)MS-ESI: 287 [MH]⁺ Elemental Analysis: Found C 57.8 H 5.2 N 19.3C₁₄H₁₄N₄O₃ 0.3H₂O Requires C 57.7 H 5.1 N 19.2% A mixture of7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (412mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was heated atreflux for 1 hour. The mixture was diluted with toluene and thevolatiles were removed by evaporation. The residue was suspended inmethylene chloride, cooled to 0° C. and aqueous sodium hydrogencarbonate solution was added. The resulting precipitate was collected byfiltration and dried under vacuum to give4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (258 mg, 59%).¹H NMR Spectrum: (DMSOd₆) 4.01(s, 3H); 4.47(m, 2H); 4.53(m, 2H); 6.89(s,1H); 7.27(s, 1H); 7.41(s, 1H); 7.49(s, 1H); 7.70(s, 1H); 8.88(s, 1H)MS-ESI: 327 [MNa]⁺ f4-Chloro-6-methoxy-7-(3-(1H-1,2,4-triazol-1-yl)propoxy)quinazoline (61mg) was reacted with 5-aminoindole in the presence of 6.2N hydrogenchloride in isopropanol (4 μl) to give4-(indol-5-ylamino)-6-methoxy-7-(3-(1H-1,2,4-triazol-1-yl)propoxy)quinazolinehydrochloride. ¹H NMR Spectrum: (DMSOd₆, CF₃COOD) 2.5(m, 2H); 4.0(s,3H); 4.3(t, 2H); 4.6(t, 2H); 6.52(d, 0.5H partly exchanged); 7.3(s, 1H);7.35(d, 1H); 7.45(s, 1H); 7.55(d, 1H); 7.8(s, 1H); 8.16(s, 1H); 8.66(s,1H); 8.77(s, 1H); 9.43(s, 1H)

EXAMPLE 266

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (144mg, 0.43 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (91 mg, 0.66 mmol) and3-fluoro-7-hydroxyquinoline (77 mg, 0.47 mmol), (prepared as describedfor the starting material in Example 157), in DMF (3 ml) was stirred at100° C. for 2 hours and then allowed to cool to ambient temperature. Thereaction mixture was evaporated to dryness and the residuechromatographed on silica eluting with methanol/dichloromethane/aqueousammonia (0.880) (5/100/1). The relevant fractions were combined andevaporated to dryness to give4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(87 mg, 44%).

¹H NMR Spectrum: (DMSOd₆) 1.37(m, 2H); 1.49(m, 4H); 1.96(m, 2H); 2.34(m,4H); 2.43(t, 2H); 4.00(s, 3H); 4.23(t, 2H); 7.38(s, 1H); 7.62(s, 1H);7.69(dd, 1H); 8.00(d, 1H); 8.12(d, 1H); 8.34(dd, 1H); 8.54(s, 1H);8.98(d, 1H)

MS (ESI): 463 (MH)⁺

EXAMPLE 267

A mixture of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218 mg,0.68 mmol), (prepared as described for the starting material in Example9), potassium carbonate (138 mg, 1.13 mmol) and3-fluoro-7-hydroxyquinoline (117 mg, 0.72 mmol), (prepared as describedfor the starting material in Example 157), in DMF (4.5 ml) was stirredat 100° C. for 4 hours and then allowed to cool to ambient temperature.The reaction mixture was evaporated to dryness and the residue taken upin dichloromethane, washed with water, brine and dried (MgSO₄). Theorganic fractions were evaporated to dryness and the residuerecrystallised from acetonitrile to give4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(86 mg, 28%).

¹H NMR Spectrum: (DMSOd₆) 1.90(m, 2H); 2.00(m, 2H); 2.27(m, 2H); 3.02(m,2H); 3.32(m, 2H); 3.59(m, 2H); 4.00(s, 3H); 4.33(t, 2H); 7.43(s, 1H);7.62(s, 1H); 7.70(dd, 1H); 7.99(d, 1H); 8.11(d, 1H); 8.35(dd, 1H);8.54(s, 1H); 8.97(d, 1H)

MS (ESI): 449 (MH)⁺

EXAMPLE 268

A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(280 mg, 0.87 mmol), (prepared as described in Example 49), potassiumcarbonate (370 mg, 2.68 mmol) and4-(1-methyl-2-oxopiperidin-4-yl)methyl-4-toluene sulphonate (260 mg,0.87 mmol) in DMF (8 ml) was stirred at 95° C. for 4 hours and allowedto cool to ambient temperature. The reaction mixture was diluted withacetone, filtered and the filtrate evaporated ‘in vacuo’ to give aresidue which was purified by column chromatography, eluting withdichloromethane/methanol/0.88 ammonia (100/8/1). The relevant fractionswere combined and evaporated ‘in vacuo’ to give an oil whichcrystallised on trituration with diethyl ether to give6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methyl-2-oxopiperidin-4-ylmethoxy)quinazoline(66 mg, 17%).

-   -   m. p. 250–251° C.

¹H NMR Spectrum: (DMSO-d₆) 1.66 (m, 1H), 2.10 (m, 2H), 2.40 (s, 3H),2.50 (m, 2H), 2.84 (s, 3H), 3.34 (m, 2H), 3.99 (s, 3H), 4.12 (d, 2H),6.12 (s, 1H), 6.86 (m, 1H), 7.25 (d, 1H), 7.30 (d, 1H), 7.38 (s, 1H),7.59 (s, 1H), 8.48 (s, 1H) and 10.98 (br s, 1H).

MS (ESI): 447 (MH)⁺

Elemental analysis Found C 66.8 H 5.9 N 12.4 C₂₅H₂₆N₄O₄ 0.2 H₂O RequiresC 66.7 H 5.9 N 12.5%

The starting material was prepared as follows:—

A solution of 4-hydroxymethyl-1-methyl-2-piperidone (120 mg, 0.84 mmol),(Yakugaku Zasshi 88, (5), 573–582, (1968)), in dichloromethane wastreated with triethylamine (187 mg, 1.85 mmol) followed byp-toluenesulphonyl chloride (176 mg, 0.92 mmol) and the mixture stirredat ambient temperature overnight. The reaction mixture was diluted withdichloromethane and washed successively with aqueous sodium hydrogencarbonate, water and brine. The dichloromethane solution was dried overmagnesium sulphate, filtered and the filtrate evaporated ‘in vacuo’ togive a dark oily residue. This was washed several times with diethylether to remove the product from insoluble impurities, the washingscombined and evaporated ‘in vacuo’ to give4-(1-methyl-2-oxopiperidin-4-yl)methyl-4-toluene sulphonate as a lightbrown oil (130 mg, 52%). This was used without further purification.

MS (ESI): 298 (MH)⁺ and impurities

EXAMPLE 269

A mixture of(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(300 mg, 0.79 mmol), and 1-methylpiperazine (0.26 ml, 2.38 mmol) in DMF(10 ml) was stirred at 70° C. for 24 hours and allowed to cool toambient temperature. The solvents were removed in vacuo and the residuepurified by silica column chromatography, gradient elution(dichloromethane, 5% methanol/95% dichloromethane,dichloromethane/methanol/0.88 ammonia (100/8/1) and evaporated in vacuoto give(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(344 mg, 91%).

¹H NMR Spectrum: (DMSO-d₆) 2.10 (s, 3H), 2.4 (m, 13H), 3.98 (s, 3H),4.06 (m, 3H), 4.90 (br s, 1H), 6.12 (s, 1H), 6.85 (dd, 1H), 7.3 (m, 2H),7.58 (s, 1H), 8.42 (s, 1H) and 10.98 (br s, 1H)

MS (ESI): 478 (MH)⁺

Elemental analysis: Found C 61.3 H 6.3 N 13.8 C₂₆H₃₀N₄O₄ 0.2H₂O.Requires C 61.9 H 6.2 N 13.4% 0.5dichloromethane

The starting material was prepared as follows:

A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(300 mg, 0.93 mmol), (prepared as described in Example 49), potassiumcarbonate (385 mg, 2.79 mmol) and (2R)-(−)-glycidyl tosylate (426 mg,2.79 mmol) in DMF (15 ml) was stirred at 60° C. for 2 hours and allowedto cool to ambient temperature. The reaction mixture was filtered andthe filtrate exaporated in vacuo. The residue was dissolved indichloromethane and washed with saturated sodium hydrogen carbonatesolution. The organic layer was then dried (MgSO₄), filtered and thesolvent removed in vacuo to give a yellow solid. This was trituratedwith ether, filtered off and dried to give(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolineas a yellow solid (185 mg, 53%).

¹H NMR Spectrum: (DMSOd₆) 2.40 (s, 3H), 2.75 (m, 1H), 2.90 (m, 1H), 3.40(m, 1H), 3.98 (s, 3H), 4.05 (m, 1H), 4.60 (m, 1H), 6.15 (s, 1H), 6.85(dd, 1H), 7.30 (m, 2H) 7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H) and10.98 (s, 1H)

MS (ESI): 378 (MH)⁺

EXAMPLE 270

A mixture of(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(300 mg, 0.79 mmol), (prepared as described for the starting material inExample 269), and diethylamine (0.25 ml, 2.38 mmol) in DMF (10 ml) wasstirred at 70° C. for 24 hours and allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residue purifiedby silica column chromatography, gradient elution (dichloromethane, 5%methanol/95% dichloromethane, dichloromethane/methanol/0.88 ammonia(100/8/1)) to give(2R)-7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(288 mg, 81%).

¹H NMR Spectrum: (DMSO-d₆) 0.95 (t, 6H), 2.10 (s, 3H), 2.4 (m, 6H), 3.98(s, 3H), 4.14 (m, 3H), 4.84 (br s, 1H), 6.12 (s, 1H), 6.85 (dd, 1H), 7.3(m, 3H), 7.58 (s, 1H), 8.42 (s, 1H) and 10.98 (br s, 1H)

MS (ESI): 448 (MH)⁺

Elemental analysis: Found C 64.3 H 6.6 N 12.0 C₂₅H₃₀N₄O₄ Requires C 64.0H 6.4 N 11.6% 0.4 dichloromethane

EXAMPLE 27

A mixture of 7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(7.76 g, 18.9 mmol), ammonium formate (17.82 g, 282 mmol) and 10%palladium on charcoal (800 mg) in DMF (350 ml) was stirred at ambienttemperature for 1 hour. The catalyst was filtered off through celite andthe cake washed with DMF. The solvent was removed in vacuo and theresidue stirred with a saturated solution of sodium hydrogen carbonatefor 2 hours. The suspension was then filtered, washed with water anddried to give 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(5.49 g, 91%).

¹H NMR Spectrum: (DMSO-d₆) 2.20 (s, 3H), 3.98 (s, 3H), 6.98 (dd, 1H),7.18 (s, 1H), 7.20 (s, 1H), 7.35 (m, 3H), 7.58 (s, 1H), 8.40 (s, 1H) and10.82 (br s, 1H)

MS (ESI): 322 (MH)⁺

The starting material was prepared as follows:

A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (7.859 g, 26.1mmol), (prepared as described for the starting material in Example 1),potassium carbonate (18.03 g, 130 mmol) and 5-hydroxy-3-methylindole(5.00 g, 34.0 mmol), (Journal of Organic Chemistry 1993, 58, 3757), inDMA (600 ml) was stirred at 75° C. for 2 hours and allowed to cool toambient temperature. The reaction mixture was filtered and the filtrateevaporated in vacuo. The crude solid was purified by silica columnchromatography, eluting with 2.5% methanol/97.5% dichloromethane to give7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (7.791 g,73%).

¹H NMR Spectrum: (CDCl₃) 2.30 (s, 3H), 4.10 (s, 3H), 5.36 (s, 2H), 7.04(m, 2H), 7.43 (m, 8H), 7.62 (s, 1H), 8.02 (s, 1H), and 8.60 (s, 1H)

MS (ESI): 412 (MH)⁺

EXAMPLE 272

A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(800 mg, 2.49 mmol), (prepared as described in Example 271), potassiumcarbonate (687 mg, 4.98 mmol) and 1-chloro-3-morpholinopropane (448 mg,2.74 mmol), (prepared as described for the starting material in Example1), in DMF (20 ml) was stirred at 80° C. for 2 hours and allowed to coolto ambient temperature. The reaction mixture was filtered and thefiltrate evaporated in vacuo. The residue was purified by silica columnchromatography, gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) and the product was recrystallised from ethanol togive6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline(570 mg, 51%).

¹H NMR Spectrum: (DMSO-d₆) 1.98 (m, 2H), 2.20 (s, 3H), 2.40 (t, 4H),2.50 (m, 2H), 3.60 (t, 4H), 3.98 (s, 3H), 4.20 (t, 2H), 6.98 (dd, 1H),7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.45 (s, 1H), and 10.82 (br s,1H)

MS (ESI): 449 (MH)⁺

Elemental analysis: Found C 64.2 H 6.0 N 11.8 C₂₅H₂₈N₄O₄ 0.7 H₂O 0.7Requires C 64.2 H 6.9 N 11.4% ethanol

EXAMPLE 273

A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(800 mg, 2.49 mmol), (prepared as described for the starting material inExample 271), potassium carbonate (1.031 g, 7.47 mmol) and4-(2-chloroethyl)morpholine hydrochloride (510 mg, 2.74 mmol) in DMF (25ml) was stirred at 80° C. for 2 hours and allowed to cool to ambienttemperature. The reaction mixture was filtered and the filtrate removedin vacuo. The residue was purified by silica column chromatography,gradient elution (dichloromethane, 5% methanol/95% dichloromethane,methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) andthe product recrystallised from ethanol to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline(510 mg, 47%).

¹H NMR Spectrum: (DMSO-d₆) 2.20 (s, 3H), 2.55 (t, 4H), 2.80 (t, 2H),3.60 (t, 4H), 3.98 (s, 3H), 4.30 (t, 2H), 6.98 (dd, 1H), 7.18 (s, 1H),7.35 (m, 2H), 7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H), and 10.82 (br s,1H)

MS (ESI): 449 (MH)⁺

Elemental analysis: Found C 64.1 H 6.3 N 12.2 C₂₄H₂₆N₄O₄ 0.4 H₂O 0.8Requires C 64.3 H 6.1 N 11.7% ethanol

EXAMPLE 274

A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(1.00 g, 3.11 mmol), (prepared as described for the starting material inExample 271), potassium carbonate (1.288 g, 9.33 mmol) and4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine(1.264 g, 3.42 mmol), (prepared as described for the starting materialin Example 10), in DMF (35 ml) was stirred at 80° C. for 2 hours andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the solvent removed in vacuo. The residue was purified bysilica column chromatography, 5% methanol/95% dichloromethane and theproduct was recrystallised from ethanol to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline(1.011 g, 63%).

¹H NMR Spectrum: (DMSO-d₆) 1.3 (m, 4H), 1.42 (s, 9H), 1.90 (d, 2H), 2.10(m, 1H), 2.28 (s, 3H), 2.80 (m, 2H), 3.98 (s, 3H), 4.08 (d, 2H), 6.98(dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.45 (s, 1H), and10.82 (br s, 1H)

MS (ESI): 519 (MH)⁺

EXAMPLE 275

A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(600 mg, 1.87 mmol), (prepared as described for the starting material inExample 271), potassium carbonate (773 mg, 5.60 mmol) and3-(1,1-dioxothiomorphlino)propoxy tosylate (1.296 g, 3.74 mmol) in DMF(30 ml) was stirred at 75° C. overnight and allowed to cool to ambienttemperature. The reaction mixture was filtered and the solvent removedin vacuo. The residue was purified by silica column chromatography,gradient elution (dichloromethane, 5% methanol/95% dichloromethane,methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) andthe product recrystallised from ethanol to give7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(525 mg, 56%).

¹H NMR Spectrum: (DMSO-d₆) 1.98 (m, 2H), 2.17 (s, 3H), 2.65 (t, 2H),2.90 (t, 4H), 3.10 (t, 4H), 3.98 (s, 3H), 4.25 (t, 2H), 6.95 (dd, 1H),7.15 (s, 1H), 7.30 (d, 1H), 7.35 (m, 2H), 7.60 (s, 1H), 8.45 (s, 1H),and 10.82 (br s, 1H)

MS (ESI): 497 (MH)⁺

Elemental analysis: Found C 58.4 H 5.5 N 11.1 C₂₅H₂₈N₄O₅S 0.8 H₂ORequires C 58.8 H 5.8 N 11.0%

EXAMPLE 276

A mixture of6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline(1.290 g, 2.49 mmol), (prepared as described in Example 274), in 25%trifluoroacetic acid/75% dichloromethane solution (75 ml) was stirred atambient temperature for 2 hours. The solvents were then removed in vacuoand the dark yellow gum triturated with concentrated ammonia. Theresulting solid was filtered off and dried to give6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(648 mg, 62%).

¹H NMR Spectrum: (DMSO-d₆) 1.35 (m, 2H), 1.80 (m, 2H), 2.05 (m, 1H),2.10 (s, 3H), 2.70 (m, 2H), 3.10 (m, 2H), 3.98 (s, 3H), 4.05 (d, 2H),6.98 (dd, 1H), 7.18 (s, 1H), 7.34 (m, 3H), 7.60 (s, 1H), 8.45 (s, 1H),and 10.82 (br s, 1H)

MS (ESI): 419 (MH)⁺

EXAMPLE 277

A mixture of6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline(460 mg, 1.10 mmol), (prepared as described in Example 276),triethylamine (5 ml) and chloroacetonitrile (0.38 ml, 6.05 mmol) inmethanol (5 ml) was stirred at ambient temperature for 24 hours. Thesolvents were removed in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) and the product recrystallised from acetonitrile togive7-(1-cyanomethylpiperidin-4-ylmethoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(178 mg, 35%).

¹H NMR Spectrum: (DMSO-d₆) 1.40 (m, 2H), 1.80 (m, 4H), 2.20 (m, 4H),2.81 (m, 2H), 3.65 (s, 2H), 3.98 (s, 3H), 4.05 (d, 2H), 6.98 (dd, 1H),7.15 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.45 (s, 1H), and 10.83 (br s,1H)

MS (ESI): 458 (MH)⁺

Elemental analysis: Found C 66.3 H 6.1 N 14.8 C₂₆H₂₇N₅O₃ 0.7 H₂ORequires C 66.4 H 6.1 N 14.9%

EXAMPLE 278

A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(1.35 g, 4.2 mmol), (prepared as described for the starting material inExample 271), potassium carbonate (1.74 g, 12.6 μmmol) and(2R)-(−)-glycidyl tosylate (1.92 g, 8.4 mmol) in DMF (25 ml) was stirredat 60° C. for 2 hours and allowed to cool to ambient temperature. Thereaction mixture was filtered and the solvent removed in vacuo. Theresidue was dissolved in dichloromethane and washed with saturatedsodium hydrogen carbonate solution. The organic layer was then dried(MgSO₄), filtered and solvent removed in vacuo to give a solid. This wastriturated with ether and the solid filtered off and dried to give(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(842 mg, 53%).

¹H NMR Spectrum: (DMSO-d₆) 2.20 (s, 3H), 2.80 (m, 1H), 2.90 (m, 1H),3.42 (m, 1H), 3.98 (s, 3H), 4.02 (m, 1H), 4.60 (m, 1H), 6.98 (dd, 1H),7.18 (s, 1H) 7.35 (m, 3H), 7.60 (s, 1H), 8.45 (s, 1H) and 10.82 (s, 1H)

MS (ESI): 378 (MH)⁺

EXAMPLE 279

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(300 mg, 0.65 mmol), (prepared as described in Example 278), andpiperidine (0.2 ml, 2.04 mmol) in DMF (5 ml) was stirred at 60° C. for24 hours and allowed to cool to ambient temperature. The solvents wereremoved in vacuo and the residue purified by silica columnchromatography, gradient elution (dichloromethane, 5% methanol/95%dichloromethane, 1% 0.880 saturated aqueous ammonia/10% methanol/89%dichloromethane)(2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(237 mg, 78%).

¹H NMR Spectrum: (DMSO-d₆) 1.38 (m, 2H), 1.50 (m, 4H), 2.34 (m, 9H),3.98 (s, 3H), 4.16 (m, 3H), 4.85 (br s, 1H), 6.98 (dd, 1H), 7.18 (s,1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 464 (MH)⁺

Elemental analysis: Found C 66.3 H 6.6 N 12.1 C₂₆H₃₀N₄O₄ 0.5 methanolRequires C 66.5 H 6.7 N 11.7%

EXAMPLE 280

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(300 mg, 0.65 mmol), (prepared as described in Example 278), andpyrrolidine (0.17 ml, 2.04 mmol) in DMF (5 ml) was stirred at 60° C. for24 hours and allowed to cool to ambient temperature. The solvents wereremoved in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(257 mg, 88%).

¹H NMR Spectrum: (DMSO-d₆) 1.65 (m, 4H), 1.98 (m, 2H), 2.20 (s, 3H),2.50 (m, 2H), 2.62 (m, 2H), 3.98 (s, 3H), 4.17 (m, 3H), 6.98 (dd, 1H),7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s,1H)

MS (ESI): 449 (MH)⁺

Elemental analysis: Found C 64.1 H 6.4 N 12.6 C₂₅H₂₈N₄O₄ 1.0 H₂ORequires C 64.4 H 6.5 N 12.0%

EXAMPLE 281

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), and1-methylpiperazine (0.31 ml, 2.78 mmol) in DMF (5 ml) was stirred at 60°C. for 24 hours and allowed to cool to ambient temperature. The solventswere removed in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(352 mg, 80%).

¹H NMR Spectrum: (DMSO-d₆) 2.10 (s, 3H), 2.20 (s, 3H), 2.40 (m, 10H),3.98 (s, 3H), 4.13 (m, 3H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H),7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 478 (MH)⁺

Elemental analysis: Found C 61.6 H 6.4 N 14.4 C₂₆H₃₁N₅O₄ 1.0 H₂O 0.25Requires C 61.6 H 6.8 N 13.9% Methanol

EXAMPLE 282

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), andmorpholine (0.24 ml, 2.78 mmol) in DMF (5 ml) was stirred at 60° C. for24 hours and allowed to cool to ambient temperature. The solvents wereremoved in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-methoxy-4-(3-methylindol-5-yloxy)quinazoline(398 mg, 93%).

¹H NMR Spectrum: (DMSO-d₆) 2.20 (s, 3H),2.44 (m, 6H),3.48 (t, 4H),3.98(s, 3H), 4.13 (m, 3H), 4.98 (br s, 1H), 6.98 (dd, 1H), 7.18 (s, 1H),7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 465 (MH)⁺

Elemental analysis: Found C 58.5 H 6.0 N 11.2 C₂₅H₂₈N₄O₅ 2.5 H₂O.Requires C 58.9 H 6.5 N 11.0%

EXAMPLE 283

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), and 2.0 Mdimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml) was stirredat 60° C. for 24 hours and allowed to cool to ambient temperature. Thesolvents were removed in vacuo and the residue purified by silica columnchromatography, gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(308 mg, 78%).

¹H NMR Spectrum: (DMSO-d₆) 2.10 (m, 9H), 2.20 (m, 2H), 3.98 (s, 3H),4.13 (m, 3H), 4.98 (br s, 1H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m,3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 423 (MH)⁺

Elemental analysis: Found C 65.5 H 6.2 N 13.2 C₂₃H₂₀N₄O₄ Requires C 65.4H 6.2 N 13.3%

EXAMPLE 284

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), anddiethylamine (0.29 ml. 2.78 mmol) in DMF (5 ml) was stirred at 60° C.for 24 hours and allowed to cool to ambient temperature. The solventswere removed in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-((N,N-diethylamino)propoxy))-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(338 mg, 81%).

¹H NMR Spectrum: (DMSO-d₆) 0.95 (t, 6H), 2.11 (s, 3H), 2.40 (m, 6H),3.98 (s, 3H), 4.13 (m, 3H), 4.84 (br s, 1H), 6.98 (dd, 1H), 7.18 (s,1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 451 (MH)⁺

Elemental analysis: Found C 64.4 H 6.6 N 12.0 C₂₅H₃₀N₄O₄ 1.0 H₂O.Requires C 64.1 H 6.9 N 12.0%

EXAMPLE 285

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), andisopropylamine (0.29 ml, 4.65 mmol) in DMF (5 ml) was stirred at 100° C.for 24 hours and allowed to cool to ambient temperature. The solventswere removed in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(307 mg, 75%).

¹H NMR Spectrum: (DMSO-d₆) 0.98 (d, 6H), 2.20 (s, 3H), 2.55–2.80 (m,3H), 3.98 (s, 3H), 4.02–4.20 (m, 3H), 4.98 (br s, 1H), 6.98 (dd, 1H),7.18 (s, 1H), 7.30–7.40 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82(br s, 1H)

MS (ESI): 437 (MH)⁺

Elemental analysis: Found C 63.3 H 6.3 N 12.4 C₂₄H₂₈N₄O₄ 1.0 H₂O.Requires C 63.4 H 6.7 N 12.3%

EXAMPLE 286

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(350 mg, 0.93 mmol), (prepared as described in Example 278), anddiisopropylamine (0.78 ml, 5.58 mmol) in DMF (10 ml) was stirred at 130°C. for 24 hours and allowed to cool to ambient temperature. The solventswere removed in vacuo and the residue purified by silica columnchromatography using gradient elution (dichloromethane, 5% methanol/95%dichloromethane, methanol/dichloromethane/0.880 saturated aqueousammonia (100/8/1)) to give(2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(398 mg, 93%).

¹H NMR Spectrum: (DMSO-d₆) 0.98 (d, 12H), 2.20 (s, 3H), 2.72 (m, 2H),3.00 (m, 2H), 3.98 (s, 3H), 4.11 (m, 3H), 6.98 (dd, 1H), 7.18 (s, 1H),7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s, 1H)

MS (ESI): 479 (MH)⁺

Elemental analysis: Found C 65.4 H 6.8 N 11.3 C₂₇H₃₄N₄O₄ 0.8 H₂O.Requires C 55.8 H 7.2 N 11.4%

EXAMPLE 287

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(100 mg, 0.28 mmol), (prepared as described in Example 278), and4-(3-aminopropyl)morpholine (0.12 ml, 0.84 mmol) in DMF (5 ml) washeated to 70° C. for 3 hours. The solvents were removed in vacuo and theresidue taken up in dichloromethane. This was washed with water, dried(MgSO₃), filtered and evaporated. The residue was purified by silicacolumn chromatography using gradient elution (dichloromethane, 5%methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80%dichloromethane) to give(2R)-7-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(67 mg, 46%).

¹H NMR Spectrum: (DMSO-d₆) 1.28 (m, 2H), 2.30 (t, 4H), 2.56 (t, 2H),2.650 (m, 4H), 3.55 (t, 4H), 3.98 (s, 3H), 4.15 (m, 3H), 6.42 (s, 1H),6.98 (dd, 1H), 7.42 (m, 4H), 7.60 (s, 1H), 8.45 (s, 1H), and 11.19(br s,1H)

MS (ESI): 508 (MH)⁺

Elemental analysis: Found C 59.7 H 6.6 N 13.4 C₂₇H₃₃N₅O₅ 1.8 H₂ORequires C 60.1 H 6.8 N 13.0%

EXAMPLE 288

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(100 mg, 0.28 mmol), (prepared as described in Example 278), and1-(3-aminopropyl)-4-methylpiperazine (132 mg, 0.84 mmol) in DMF (5 ml)was heated to 70° C. for 3 hours. The solvents were removed in vacuo andthe residue taken up in dichloromethane. This was washed with water,dried (MgSO₄), filtered and evaporated. The residue was purified bysilica column chromatography using gradient elution (dichloromethane, 5%methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80%dichloromethane) to give(2R)-7-(2-hydroxy-3-(344-methylpiperazin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(44 mg, 31%).

¹H NMR Spectrum: (DMSO-d₆) 1.55 (m, 2H), 2.10 (s, 3H), 2.30 (t, 8H),2.62 (m, 6H), 3.98 (s, 3H), 4.12 (m, 3H), 6.42 (s, 1H), 6.98 (dd, 1H),7.42 (m, 4H), 7.60 (s, 1H), 8.45 (s, 1H), and 11.19(br s, 1H)

MS (ESI): 521 (MH)⁺

Elemental analysis: Found C 61.3 H 7.3 N 16.1 C₂₈H₃₆N₆O₄ 1.6 H₂ORequires C 61.2 H 7.2 N 16.3%

EXAMPLE 289

A mixture of(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(70 mg, 0.19 mmol), (prepared as described in Example 278), and1-(3-aminopropyl)pyrrolidine (74 mg, 0.58 mmol) in DMF (5 ml) was heatedto 60° C. overnight. The solvents were removed in vacuo and the residuepurified by column chromatography using gradient elution(dichloromethane, 5% methanol/95% dichloromethane, 20% methanolicammonia (7M)/80% dichloromethane) to give(2R)-7-(2-hydroxy-3-(3-(pyrrolidin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline(64 mg, 68%).

¹H NMR Spectrum: (DMSO-d₆) 1.60 (m, 6H), 2.25 (m, 4H), 2.60 (m, 4H),3.08 (m, 2H), 3.98 (s, 3H), 4.12 (m, 3H), 6.42 (s, 1H), 6.98 (dd, 1H),7.34 (m, 4H), 7.58 (s, 1H), 8.42 (s, 1H), and 11.80(br s, 1H)

MS (ESI): 492 (MH)⁺

EXAMPLE 290

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (380mg, 1.13 mmol), (prepared as described for the starting material inExample 67), potassium carbonate (469 mg, 3.4 mmol),4-bromo-5-hydroxyindole (240 mg, 1.13 mmol) and DMA (4.0 ml) werestirred at 90° C. for 3 hours and allowed to cool to ambienttemperature. The reaction mixture was filtered and the filtrateevaporated under vacuum. The residue was purified by columnchromatography eluting with dichloromethane/methanolic ammonia (7M)(95/5) to give an oil. This oil was further purified by columnchromatography eluting with dichloromethane/methanol (60/40) to give4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(256 mg, 44%).

¹H NMR Spectrum: (CDCl₃) 1.47 (m, 2H), 1.60 (m, 4H), 2.14 (m, 2H), 2.44(m, 4H), 2.54 (t, 2H), 4.08 (s, 3H), 4.27 (t, 2H), 6.67 (m, 1H), 7.15(d, 1H), 7.32 (t, 1H), 7.36 (s, 1H), 7.42 (d, 1H), 7.69 (s, 1H) 8.55 (brs, 1H) and 8.62 (s, 1H)

MS (ESI): 511, 513 (MH)⁺

Elemental analysis Found C 58.2 H 5.3 N 10.8 C₂₅H₂₇BrN₄O₃ 0.25 H₂O,Requires C 58.2 H 5.4 N 10.9%

The starting material was prepared as follows:

Ethyl 4-bromo-5-hydroxyindole-2-carboxylate (1.49 g, 5 mmol.), (Jnl.Org. Chem. 1984, 49, 4761), was dissolved in ethanol (10 ml) and water(3.5 ml). Potassium hydroxide (840 mg) was added and the mixture stirredat 50° C. under an atmosphere of nitrogen for 1 hour then cooled toambient temperature. The solvent was evaporated and the residueredissolved in water (25 ml). 2M Aqueous hydrochloric acid was addeduntil the reaction mixture was at pH4, giving a precipitate which wasfiltered off, washed with water and dried under vacuum to give4-bromo-5-methoxyindole-2-carboxylic acid (1.30, 96%).

¹H NMR Spectrum: (DMSO-d₆) 3.83 (s, 3H), 6.90 (d, 1H), 7.16 (d, 1H),7.40 (d, 1H). 11.88 (br s, 1H) and 13.19 (br s, 1H)

MS (ESI): 268, 270 (M-H)

4-Bromo-5-methoxyindole-2-carboxylic acid (1.25 g, 4.19 mmol), quinoline(15 ml) and copper chromite (313 mg) were mixed together. Nitrogen wasgently bubbled through the mixture for 5 minutes, then the mixtureheated quickly to 245° C. under an atmosphere of nitrogen. After 90minutes the mixture was cooled to ambient temperature diluted with ethylacetate (100 ml) and washed with 2M aqueous hydrochloric acid (60 ml).The ethyl acetate layer was filtered, the filtrate dried (MgSO₄) and thesolvent evaporated. The residue was purified by silica columnchromatography eluting with dichloromethane/hexane (1/1) to give4-bromo-5-methoxyindole (635 mg, 60%).

¹H NMR Spectrum (CDCl₃) 3.94 (s, 3H), 6.55 (m, 1H), 6.93 (d, 1H), 7.27(m, 2H). 8.18 (br s, 1H)

MS (ESI): 224, 226 (M-H)⁻

A solution of 4-bromo-5-methoxyindole (540 mg, 2.4 mmol) indichloromethane (12 ml) was cooled to −40° C. under an atmosphere ofnitrogen. Boron tribromide (4.8 ml of a 1M solution in dichloromethane,4.8 mmol) was added dropwise then the mixture warmed to ambienttemperature and stirred for 1 hour. The mixture was diluted withdichloromethane (5 ml) and washed with 2M aqueous hydrochloric acid (3ml). The organic layer was separated, dried (MgSO₄) and evaporated togive a dark oil. This was purified by silica column chromatographyeluting with dichloromethane/ethyl acetate (8/2) to give4-bromo-5-hydroxyindole (295 mg, 55%).

¹H NMR Spectrum: (CDCl₃) 6.46 (m, 1H), 7.92 (d, 1H), 7.22 (m, 2H), 8.80(br s, 1H)

MS (ESI): 210, 212 (M-H)⁻

EXAMPLE 291

Nitrogen was bubbled through a mixture of4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (335 mg, 0.68mmol), (prepared as described for the starting material in Example 67),potassium carbonate (281.5 mg, 2.04 mmol), 5-hydroxy-1methylindole (100mg, 0.68 mmol) and DMA (4.0 ml) for 5 minutes. The mixture was thenstirred at 90° C. for 4 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated under vacuum. The residue waspurified by trituration with methanol then water to give6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline(148 mg, 49%).

¹H NMR Spectrum: (DMSO-d₆) 1.38 (m, 2H), 1.51 (m, 4H), 1.93 (m, 2H),2.35 (m, 4H), 2.41 (t, 2H), 3.83 (s, 3H), 3.97 (s, 3H), 4.24 (t, 2H),6.42 (d, 1H), 7.06 (dd, 1H), 7.33 (s, 1H), 7.42 (m, 2H), 7.50 (d, 1H),7.59 (s, 1H) and 8.47 (s, 1H)

MS (ESI): 447 (MH)⁺

Elemental analysis Found C 69.5 H 6.8 N 12.5 C₂₆H₃₀N₄O₃ Requires C 69.9H 6.8 N 12.6%

The starting material was prepared as follows:

A solution of 5-benzyloxy-1-methylindole (3.5 g, 15.7 mmol), in ethanol(100 ml) was hydrogenated at ambient temperature and 1 atmospherepressure hydrogen for 4 hours using 10% palladium on carbon (0.5 g) ascatalyst. The catalyst was filtered off and the filtrate evaporated invacuo. The residue was purified by silica column chromatography elutingwith ethyl acetate/dichloromethane (10/90) to give5-hydroxy-1-methylindole (2.1 g, 97%).

MS (ESI): 146 (M-H)⁻

NMR Spectrum: (CDCl₃) 3.74 (s, 3H), 4.50 (S, 1H), 6.33 (d, 1H), 6.79(dd, 1H), 7.00 (m, 2H), 7.17 (d, 1H)

EXAMPLE 292

A mixture of(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300mg, 0.83 mmol), and pyrrolidine (176 mg, 2.48 mmol) in DMF (5 ml) wasstirred at 75° C. for 3 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The solvents were removed invacuo and the residue purified on silica gel, gradient elution withdichloromethane, dichloromethane/methanol (95/5),dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(326 mg, 87%).

¹H NMR Spectrum: (CDCl₃) 1.80 (m, 4H), 2.56 (m, 3H), 2.71 (m, 2H), 2.87(m, 1H), 4.04 (s, 3H), 4.23 (m, 3H), 6.59 (m, 1H), 7.07 (dd, 1H), 7.25(m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.50 (d, 1H), 7.61 (s, 1H), 8.3.0(br s, 1H) and 8.60 (s, 1H)

MS (ESI): 435(MH)⁺

Elemental analysis Found C 63.4 H 5.9 N 12.3 C₂₄H₂₆N₄O₄.1H₂O Requires C63.7 H 6.2 N 12.4%

The starting material was prepared as follows:

Nitrogen was bubbled through a mixture of7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol),(prepared as described for the starting material in Example 107),potassium carbonate (4.14 g, 30 mmol) and (2R)-(−)-glycidyl tosylate(4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. The mixture was thenstirred at 60° C. for 2 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated in vacuo. The residue was purifiedby column chromatography on silica by gradient elution withdichloromethane/methanol (100/0 to 95/5), to give(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline as ayellow solid (1.92 g, 53%).

¹H NMR Spectrum: (DMSOd₆) 2.75 (m, 1H), 2.89 (m, 1H), 3.44 (m, 1H), 3.97(s, 3H), 4.06 (m, 1H), 4.58 (dd, 1H), 6.44 (m, 1H), 6.95 (dd, 1H), 7.40(m, 4H) 7.62 (s, 1H), 8.47 (s, 1H), 11.19 (br s 1H)

MS (ESI): 364 (MH)⁺

EXAMPLE 293

Using an analogous procedure to that described in Example 292,(2R)4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300mg, 0.83 mmol), (prepared as described for the starting material inExample 292), was reacted with morpholine (211 mg, 2.49 mmol) to give(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(338 mg, 85%).

¹H NMR Spectrum: (CDCl₃) 2.48 (m, 2H), 2.624 (m, 2H), 2.68 (m, 2H), 3.78(m, 4H), 4.04 (s, 3H), 4.24 (m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H), 7.29(m, 1H), 7.34 (s, 1H), 7.46 (d, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 8.31(br s, 1H) and 8.62 (s, 1H)

MS (ESI): 451(MH)⁺

Elemental analysis Found C 60.3 H 5.9 N 12.3 C₂₄H₂₆N₄O₅.1.5H₂O RequiresC 60.4 H 6.1 N 11.7%

EXAMPLE 294

Using an analogous procedure to that described in Example 292,(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300mg, 0.83 mmol), (prepared as described for the starting material inExample 292), was reacted with piperidine (211 mg, 2.49 mmol) to give(2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(325 mg, 86%).

¹H NMR Spectrum: (CDCl₃) 1.47 (m, 2H), 1.61 (m, 4H), 2.39 (m, 2H), 2.54(d, 2H), 2.64 (m, 2H), 4.04 (s, 3H), 4.24 (m, 3H), 6.58 (m, 1H), 7.08(dd, 1H), 7.29 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.48 (d, 1H), 7.62(s, 1H), 8.28 (br s, 1H) and 8.60 (s, 1H)

MS (ESI): 449 (MH)⁺

Elemental analysis Found C 65.9 H 6.3 N 12.3 C₂₅H₂₈N₄O₄.0.5H₂O RequiresC 65.6 H 6.4 N 12.3%

EXAMPLE 295

A mixture of(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300mg, 0.83 mmol), (prepared as described for the starting material inExample 292), and dimethylamine (1.24 ml of a 2M solution in THF, 2.48mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under anatmosphere of nitrogen then allowed to cool to ambient temperature. Thesolvents were removed in vacuo and the residue purified by triturationwith methanol to give(2R)-7-(2-hydroxy-3-dimethylaminopropoxy)4-(indol-5-yloxy)-6-methoxyquinazoline(265 mg, 63%).

¹H NMR Spectrum: (DMSOd₆) 2.21 (s, 6H), 2.38 (m, 2H), 3.97 (s, 3H),4.073 (m, 2H), 4.21 (m, 1H), 4.96 (d, 1H), 6.43 (m, 1H), 6.97 (dd, 1H),7.37 (s, 1H), 7.43 (m, 3H), 7.62 (s, 1H), 8.48 (s, 1H) and 11.20 (br s,1H)

MS (ESI): 409(MH)⁺

Elemental analysis Found C 62.8 H 5.8 N 13.2 C₂₂H₂₄N₄O₄.0.7H₂O RequiresC 62.8 H 6.1 N 13.3%

EXAMPLE 296

A mixture of(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300mg, 0.83 mmol), (prepared as described for the starting material inExample 292), and diisopropylamine (1.35 ml, 9.7 mmol) in DMF (5 ml) wasstirred at 70° C. for 19 hours under an atmosphere of nitrogen thenallowed to cool to ambient temperature. The solvents were removed invacuo and the residue purified on silica gel using gradient elution withdichloromethane, dichloromethane/methanol (95/5),dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give(2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(343 mg, 86%).

¹H NMR Spectrum: (CDCl₃) 1.08 (m, 12H), 1.57 (m, 1H), 1.75 (m, 1H), 3.10(m, 2H),4.04 (s, 3H), 4.16 (m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H), 7.26(m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.50 (d, 1H), 7.61 (s, 1H), 8.32(br s, 1H) and 8.61 (s, 1H)

MS (ESI): 465(MH)⁺

Elemental analysis Found C 64.8 H 6.8 N 11.9 C₂₆H₃₂N₄O₄. 1.0H₂O RequiresC 64.6 H 7.0 N 11.6%

EXAMPLE 297

A mixture of(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), and pyrrolidine (60 mg, 0.84 mmol) in DMF (5 ml) wasstirred at 75° C. for 3 hours under an atmosphere of nitrogen and thenallowed to cool to ambient temperature. The solvents were removed invacuo and the residue purified on silica gel, gradient elution withdichloromethane, dichloromethane/methanol (95/5),dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give(2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(114 mg, 92%).

¹H NMR Spectrum: (CDCl₃) 1.80 (m, 4H), 2.56 (m, 3H), 2.71 (m, 2H), 2.86(m, 1H), 4.04 (s, 3H), 4.23 (m, 3H), 6.59 (m, 1H), 7.07 (dd, 1H), 7.25(m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.50 (d, 1H), 7.61 (s, 1H), 8.30(br s, 1H) and 8.60 (s, 1H)

MS (ESI): 435(MH)⁺

Elemental analysis Found C 64.7 H 6.0 N 12.6 C₂₄H₂₆N₄O₄.0.5H₂O RequiresC 64.9 H 6.1 N 12.7%

The starting material was prepared as follows:

Nitrogen was bubbled through a mixture of7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol),(prepared as described for the starting material in Example 107),potassium carbonate (4.14 g, 30 mmol) and (2S)-(+)-glycidyl tosylate(4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. This mixture was thenstirred at 60° C. for 2 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated in vacuo. The residue was purifiedby column chromatography on silica by gradient elution withdichloromethane/methanol (100/0 to 95/5), to give after removal of thesolvents in vacuo and trituration of the residue with ether,(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (1.88g, 52%) as a yellow solid.

¹H NMR Spectrum: (DMSOd₆) 2.75 (m, 1H), 2.89 (m, 1H), 3.44 (m, 1H), 3.97(s, 3H), 4.06 (m, 1H), 4.58 (dd, 1H), 6.44 (m, 1H), 6.95 (dd, 1H), 7.46(m, 4H) 7.62 (s, 1H), 8.47 (s, 1H) and 11.19 (br s 1H)

MS (ESI):364 (MH)⁺

EXAMPLE 298

Using an analogous procedure to that described in Example 297,(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 297), was reacted with morpholine (73.2 mg, 0.84 mmol) to give(2S)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(82 mg, 63%).

¹H NMR Spectrum: (CDCl₃) 2.48 (m, 2H), 2.62 (m, 2H), 2.68 (m, 2H), 3.78(m, 4H), 4.04 (s, 3H), 4.29 (m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H), 7.29(m, 1H), 7.34 (s, 1H), 7.46 (d, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 8.31(br s, 1H) and 8.62 (s, 1H)

MS (ESI): 451 (MH)⁺

Elemental analysis Found C 61.7 H 5.7 N 11.8 C₂₄H₂₆N₄O₅.1.0H₂O RequiresC 61.5 H 6.0 N 12.0%

EXAMPLE 299

Using an analogous procedure to that described in Example 297,(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 297), was reacted with piperidine (70 mg, 0.83 mmol), to give(2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(93 mg, 73%).

¹H NMR Spectrum: (CDCl₃) 1.47 (m, 2H), 1.61 (m, 4H), 2.39 (m, 2H), 2.54(d, 2H), 2.64 (m, 2H), 4.04 (s, 3H), 4.29 (m, 3H), 6.58 (m, 1H), 7.08(dd, 1H), 7.29 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.48 (d, 1H), 7.62(s, 1H), 8.28 (br s, 1H) and 8.60 (s, 1H)

MS (ESI): 449 (MH)⁺

Elemental analysis Found C 65.8 H 6.2 N 12.2 C₂₅H₂₈N₄O₄.0.5H₂O RequiresC 65.6 H 6.4 N 12.3%

EXAMPLE 300

A mixture of(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 297), and dimethylamine (0.42 ml of a 2M solution in THF, 0.84mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under anatmosphere of nitrogen and then allowed to cool to ambient temperature.The solvents were removed in vacuo and the residue purified bytrituration with methanol to give(2S)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(100 mg, 85%).

¹H NMR Spectrum: (DMSOd₆) 2.21 (s, 6H), 2.38 (m, 2H), 3.97 (s, 3H),4.083 (m, 2H), 4.21 (m, 1H), 4.96 (d, 1H), 6.43 (m, 1H), 6.97 (dd, 1H),7.37 (s, 1H), 7.43 (m, 3H), 7.62 (s, 1H), 8.48 (s, 1H) and 11.20 (br s,1H)

MS (ESI): 409(MH)⁺

Elemental analysis Found C 63.6 H 6.0 N 13.3 C₂₂H₂₄N₄O₄.0.5H₂O RequiresC 63.3 H 6.0 N 13.4%

EXAMPLE 301

A mixture of(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 297), and diisopropylamine (0.45 ml, 3.2 mmol) in DMF (5 ml) wasstirred at 70° C. for 19 hours under an atmosphere of nitrogen and thenallowed to cool to ambient temperature. The solvents were removed invacuo and the residue purified on silica gel, using gradient elutionwith dichloromethane/methanol (100/0 to 95/5),dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give(2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline(43 mg, 33%).

¹H NMR Spectrum: (CDCl₃) 1.08 (m, 12H), 1.57 (m, 1H), 1.759 (m, 1H),3.10 (m, 2H), 4.04 (s, 3H), 4.16 (m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H),7.26 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H), 7.50 (d, 1H), 7.61 (s, 1H),8.32 (br s, 1H) and 8.61 (s, 1H)

MS (ESI): 465(MH)⁺

Elemental analysis Found C 67.2 H 7.0 N 11.9 C₂₆H₃₂N₄O₄ Requires C 67.2H 6.9 N 12.1%

EXAMPLE 302

A mixture of(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 292), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at75° C. for 18 hours under an atmosphere of nitrogen and then allowed tocool to ambient temperature. The mixture was filtered and the filtrateevaporated in vacuo. The residue was purified by silica gelchromatography, gradient elution with dichloromethane/methanolic ammonia(7M) (100/0 to 90/10) to give(2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline(82 mg, 68%).

¹H NMR Spectrum: (DMSOd₆) 0.98 (m, 6H), 2.68 (m, 3H), 3.96 (m, 4H), 4.13(m, 2H), 5.06 (br s, 1H), 6.44 (s, 1H), 6.98 (dd, 1H), 7.439 (m, 4H),7.60 (s, 1H), 8.46 (s, 1H) and 11.22 (s, 1H)

MS (ESI): 423(MH)⁺

Elemental analysis Found C 63.6 H 6.4 N 12.9 C₂₃H₂₆N₄O₄.0.6H₂O RequiresC 63.8 H 6.3 N 12.9%

EXAMPLE 303

A mixture of(2S)4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100mg, 0.28 mmol), (prepared as described for the starting material inExample 297), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at75° C. for 18 hours under an atmosphere of nitrogen and then allowed tocool to ambient temperature. The mixture was filtered and the filtrateevaporated in vacuo. The residue was purified by silica gelchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 90/10) to give(2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline(66 mg, 56%).

¹H NMR Spectrum: (DMSOd₆) 0.985 (m, 6H), 2.68 (m, 3H), 3.96 (m, 4H),4.13 (m, 2H), 5.06 (br s, 1H), 6.44 (s, 1H), 6.98 (dd, I H), 7.43 (m,4H), 7.60 (s, 1H), 8.46 (s, 1H) and 11.22 (s, 1H)

MS (ESI): 423(MH)⁺

Elemental analysis Found C 63.1 H 6.3 N 12.7 C₂₃H₂₆N₄O₄.0.9 H₂O RequiresC 63.0 H 6.4 N 12.8%

EXAMPLE 304

A mixture of(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2ylmethoxy)quinazoline(250 mg, 0.66 mmol), and pyrrolidine (1.5 ml) in THF (10 ml) was stirredat 75° C. for 3 hours under an atmosphere of nitrogen and then allowedto cool to ambient temperature. The mixture was filtered and thefiltrate evaporated in vacuo. The residue was purified by silica gelchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 90/10) to give(2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-methoxy-4-(2-methylindol-5-yloxy)quinazoline(106 mg, 36%).

¹H NMR Spectrum: (DMSOd₆) 1.60 (s, 4H), 2.38 (s, 3H), 2.57 (m, 6H), 4.11(m, 6H), 4.95 (d, 1H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.29 (m, 2H), 7.37(s, 1H), 7.59 (s, 1H), 8.48 (s, 1H) and 11.00 (s, 1H)

MS (ESI): 450 (MH)⁺

Elemental analysis Found C 67.0 H 6.5 N 12.0 C₂₅H₂₈N₄O₄.0.1 H₂O RequiresC 66.7 H 6.3 N 12.4%

The starting material was prepared as follows:

A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(300 mg, 0.93 mmol), (prepared as described in Example 49), potassiumcarbonate (385 mg, 2.79 mmol) and (2S)-(−)-glycidyl tosylate (426 mg,2.79 mmol) in DMF (15 ml) was stirred at 60° C. for 2 hours and allowedto cool to ambient temperature. The reaction mixture was filtered andthe filtrate evaporated in vacuo. The residue was dissolved indichloromethane and washed with saturated sodium hydrogen carbonatesolution. The organic layer was then dried (MgSO₄), filtered and thesolvent removed in vacuo to give a yellow solid. This was trituratedwith ether, filtered off and dried to give(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolineas a yellow solid (277 mg, 78%).

¹H NMR Spectrum: (DMSO) 2.40 (s, 3H), 2.75 (m, 1H), 2.90 (m, 1H), 3.40(m, 1H), 3.98 (s, 3H), 4.05 (m, 1H), 4.60 (m, 1H), 6.15 (s, 1H), 6.85(dd, 1H), 7.30 (m, 3H) 7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H) and10.98 (s, 1H)

MS (ESI): 378 (MH)⁺

EXAMPLE 305

A mixture of the(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(250 mg, 0.66 mmol), (prepared as described for the starting material inExample 269), and pyrrolidine (1.5 ml) in THF (10 ml) was stirred at 75°C. for 3 hours under an atmosphere of nitrogen and then allowed to coolto ambient temperature. The mixture was filtered and the filtrateevaporated in vacuo. The residue was purified by silica gelchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 90/10) to give(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)4-methoxy-4-(2-methylindol-5-yloxy)quinazoline(165 mg, 55%).

¹H NMR Spectrum: (DMSOd₆) 1.60 (s, 4H), 2.38 (s, 3H), 2.57 (m, 6H), 4.11(m, 6H), 4.95 (d, 1H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.29 (m, 2H), 7.37(s, 1H), 7.59 (s, 1H), 8.48 (s, 1H) and 11.00 (s, 1H)

MS (ESI): 450 (MH)⁺

Elemental analysis Found C 66.8 H 6.3 N 12.4 C₂₅H₂₈N₄O₄.0.1 H₂O RequiresC 66.7 H 6.3 N 12.4%

EXAMPLE 306

A mixture of(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(250 mg, 0.66 m.mol), (prepared as described for the starting materialin Example 304), and isopropylamine (1.5 ml) in THF (10 ml) was stirredat 75° C. for 18 hours under an atmosphere of nitrogen and then allowedto cool to ambient temperature. The mixture was filtered and thefiltrate evaporated in vacuo. The residue was purified by silica gelchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 90/10) to give(2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(210 mg, 73%).

¹H NMR Spectrum: (DMSOd₆) 0.99 (d, 6H), 2.39 (s, 3H), 2.66 (m, 3H), 4.07(m, 6H), 5.08 (d, 1H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.29 (m, 2H), 7.37(s, 1H), 7.58 (s, 1H), 8.49 (s, 1H) and 11.03 (s, 1H)

MS (ESI): 437 (MH)⁺

Elemental analysis Found C 64.3 H 6.4 N 12.3 C₂₄H₂₈N₄O₄.0.5 H₂O RequiresC 64.7 H 6.6 N 12.6%

EXAMPLE 307

A mixture of(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(250 mg, 0.66 mmol), (prepared as described for the starting material inExample 269), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at75° C. for 18 hours under an atmosphere of nitrogen and then allowed tocool to ambient temperature. The mixture was filtered and the filtrateevaporated in vacuo. The residue was purified by silica gelchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 90/10) to give(2R)-7-(2-hydroxy-3-isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline(243 mg, 84%).

¹H NMR Spectrum: (DMSOd₆): 0.99 (d, 6H), 2.39 (s, 3H), 2.66 (m, 3H),4.07 (m, 6H), 5.08 (d, 1H), 6.14 (s, 1H), 6.88 (dd, 1H), 7.29 (m, 2H),7.37 (s, 1H), 7.58 (s, 1H), 8.49 (s, 1H) and 11.03(s, 1H)

MS (ESI): 437 (MH)⁺

Elemental analysis Found C 64.3 H 6.5 N 12.3 C₂₄H₂₈N₄O₄.0.5 H₂O RequiresC 64.7 H 6.6 N 12.6%

EXAMPLE 308

Nitrogen was bubbled through a mixture of4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (400 mg, 1.19mmol), (prepared as described for the starting material in Example 1),potassium carbonate (476 mg, 3.45 mmol), 5-hdyroxy-1-methylindole (220mg, 1.5 mmol), (prepared as described for the starting material inExample 291), and DMA (5.0 ml) for 5 minutes. The mixture was thenstirred at 90° C. for 3 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated in vacuo. The residue was purifiedby trituration with methanol to give6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline(312 mg, 59%).

¹H NMR Spectrum: (CDCl₃) 2.13 (m, 2H), 1.48 (t, 4H), 1.57 (t, 2H), 3.72(t, 4H), 3.84 (s, 3H), 4.05 (s, 3H), 4.3 (t, 2H), 6.50 (d, 1H),7.08–7.13 (m, 2H), 7.32 (s, 1H), 7.37 (s, 1H), 7.47 (d, 1H), 7.62 (s,1H) 8.59 (s, 1H)

MS (ESI): 449 (MH)⁺

Elemental analysis Found C 66.5 H 6.4 N 12.3 C₂₅H₂₈N₄O₄.0.1 H₂O RequiresC 66.7 H 6.3 N 12.4%

EXAMPLE 309

Nitrogen was bubbled through a mixture of4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (400 mg, 1.24mmol), (prepared as described for the starting material in Example 180),potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231mg, 1.57 mmol), (prepared as described for the starting material inExample 291), and DMA (5.0 ml) for 5 minutes. The mixture was thenstirred at 90° C. for 3 hours under an atmosphere of nitrogen and thenallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated in vacuo. The residue was purifiedby trituration with methanol to give6-methoxy-4-(1-methylindol-5-yloxy)-7-(2-piperidinopropoxy)quinazoline(447 mg, 83%).

¹H NMR Spectrum: (CDCl₃) 1.47 (m, 2H), 1.64 (m, 4H), 2.57 (t, 4H) 2.94(t, 2H), 3.83 (s, 3H), 4.05 (s, 3H), 4.34 (t, 2H), 6.49 (d, 1H), 7.10(m, 2H), 7.32 (s, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.62 (s, 1H) 8.60 (s,1H)

MS (ESI): 433 (MH)⁺

Elemental analysis Found C 69.2 H 6.7 N 12.7 C₂₅H₂₈N₄O₃ Requires C 69.4H 6.5 N 13.0%

EXAMPLE 310

Nitrogen was bubbled through a mixture of4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400 mg,1.24 mmol), (prepared as described for the starting material in Example9), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole(231 mg, 1.57 mmol), (prepared as described for the starting material inExample 291), and DMA (5.0 ml) for 5 minutes. The mixture was thenstirred at 90° C. for 3 hours under an atmosphere of nitrogen andallowed to cool to ambient temperature. The reaction mixture wasfiltered and the filtrate evaporated in vacuo. The residue was purifiedby column chromatography, gradient elution, withdichloromethane/methanolic ammonia (7M), (100/0 to 90/10) to give6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline(247 mg, 44%).

¹H NMR Spectrum: (CDCl₃) 1.81 (m, 4H), 2.18 (m, 2H), 2.56 (m, 4H), 2.69(t. 2H), 3.82 (s, 3H), 4.05 (s, 3H), 4.30 (t, 2H), 6.45 (d, 1H), 7.09(dd, 2H), 7.31 (s, 1H), 7.38 (d, 1H), 7.47 (d, 1H), 7.62 (s, 1H) and8.59 (s, 1H)

MS (ESI):433 (MH)⁺

Elemental analysis Found C 66.5 H 6.3 N 12.4 C₂₅H₂₈N₄O₃ 0.1 dichloro-Requires C 66.7 H 6.6 N 12.4% methane + 0.7 H₂O

EXAMPLE 311

Nitrogen was bubbled through a mixture of4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (114 mg, 0.34mmol), (prepared as described for the starting material in Example 67),potassium carbonate (141 mg, 1.02 mmol), 5-hydroxy-4-nitroindole (60.5mg, 0.34 mmol) and DMA (8.5 ml) for 5 minutes at ambient temperature.This mixture was then stirred at 90° C. for 4 hours under an atmosphereof nitrogen and allowed to cool to ambient temperature. The reactionmixture was filtered and the filtrate evaporated in vacuo. The residuewas purified by silica column chromatography using gradient elution withdichloromethane/methanol (100/0 to 95/5) followed bydichloromethane/methanolic ammonia (7M) (95/5) to give a partiallypurified oil. This oil was further purified by silica columnchromatography, gradient elution with ethyl acetate/methanolic ammonia(95/5 to 80/20) to give6-methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (63mg, 39%).

¹H NMR Spectrum: (CDCl₃) 1.46 (m, 2H), 1.60 (m, 4H), 2.16 (m, 2H), 2.43(m, 4H), 2.54 (t, 2H), 3.85 (s, 3H), 4.33 (t, 2H), 7.04 (d, 1H), 7.10(s, 1H), 7.47 (s, 1H), 7.57 (d, 1H), 7.83 (d, 1H), 7.95 (d, 1H) and 9.09(s, 1H)

MS (ESI): 478 (MH)⁺

Elemental analysis Found C 62.5 H 5.8 N 14.7 C₂₅H₂₇N₅O₅ Requires C 62.9H 5.7 N 14.7%

The starting material was prepared as follows:

A mixture of ethyl 5-methoxyindole-2-carboxylate (8.15 g, 37.2 mmol),(prepared by the method described in Heterocycles Vol. 43, No. 2, p.263–266), nitric acid adsorbed on silica gel (24 g) and dichloromethane(150 ml) was stirred at ambient temperature for 18 hours. Thedichloromethane was removed in vacuo and the product washed off thesilica with acetone. The acetone was evaporated in vacuo. The residuewas treated again with nitric acid on silica (1 g) as above and the workup procedure repeated to give ethyl5-hydroxy-4-nitroindole-2-carboxylate (5.8 g, 59%).

¹H NMR Spectrum: (DMSOd₆) 1.33 (t, 3H), 3.95 (s, 3H), 4.35 (q, 2H), 7.19(d, 1H), 7.35 (d, 1H), 7.75 (d, 1H) and 12.45 (br s, 1H)

Ethyl 5-hydroxy-4-nitroindole-2-carboxylate (1.0 g, 3.8 mmol.) wassuspended in a mixture of ethanol (20 ml) and water (5 ml). Potassiumhydroxide (840 mg) was added and the mixture stirred at 50° C. under anatmosphere of nitrogen for 1 hour then cooled to ambient temperature.The solvent was evaporated in vacuo and the residue re-dissolved inwater (25 ml). The pH was adjusted to pH2 using aqueous hydrochloricacid (2M). The resulting precipitate was filtered off, washed with waterand dried in vacuo to give 5-methoxy-4-nitroindole-2-carboxylic acid(790 mg). This was used without further purification.

The crude 5-methoxy-4-nitroindole-2-carboxylic acid (720 mg, 3.05 mmol),quinoline (9 ml) and copper chromite (180 mg) were stirred together.Nitrogen was gently bubbled through the mixture for 5 minutes, then themixture was heated quickly to 225° C., and stirred at this temperaturefor 40 minutes under an atmosphere of nitrogen. The mixture was cooledto ambient temperature diluted with ethyl acetate (80 ml) and theinsoluble material filtered off. The filtrate was extracted twice withaqueous hydrochloric acid (2M) and then with saturated aqueous sodiumhydrogen carbonate solution. The ethyl acetate layer was dried (MgSO₄),evaporated and the residue purified by silica column chromatographyeluting with dichloromethane to give 5-methoxy-4-nitroindole (129 mg,22%).

¹H NMR Spectrum: (CDCl₃) 3.99 (s, 3H), 6.88 (t, 1H), 6.97 (d, 1H), 7.37(t, 1H). 7.55 (d, 1H) and 8.38 (br s, 1H)

MS (ESI): 193 (MH)⁺

A solution of 5-methoxy-4-nitroindole (110 mg, 0.57 mmol) indichloromethane (12 ml) was cooled to −30° C. under an atmosphere ofnitrogen. Boron tribromide (0.74 ml of a 1M solution in dichloromethane,0.74 mmol) was added dropwise then the mixture warmed to ambienttemperature and stirred for 1 hour. The mixture was cooled to 5° C.,diluted with dichloromethane (5 ml), and water (10 ml). After stirringfor 5 minutes the insoluble material was filtered off and thedichloromethane layer separated, dried (MgSO₄), and evaporated to give adark oil which was and purified by silica column chromatography elutingwith dichloromethane to give 5-hydroxy-4-nitroindole (68 mg, 67%).

¹H NMR Spectrum: (CDCl₃) 6.95 (d, 1H), 7.29 (m, 1H), 7.43 (t, 1H), 7.63(d, 1H) and 11.60 (br s, 1H)

MS (ESI): 177 (M-H)⁻

EXAMPLE 312

6-Methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (45mg 0.094 mmol), (prepared as described in Example 311), ethanol (20 ml)and 10% palladium on charcoal were hydrogenated at 45° C. and 1atmosphere pressure of hydrogen for 3.5 hours. The mixture was cooled toambient temperature, the catalyst filtered off and the filtrateevaporated in vacuo. The residue was purified by silica columnchromatography using gradient elution with dichloromethane/methanolicammonia (7M) (100/0 to 95/5), to give4-(4-amino-indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline(39 mg, 87%).

¹H NMR Spectrum: (CDCl₃) 1.39(m, 2H), 1.50 (m, 4H), 1.96 (m, 2H), 2.35(m, 4H), 2.43 (t, 2H), 3.80 (s, 3H), 4.28 (t, 2H), 4.84 (br s, 2H), 6.68(d, 1H), 6.78 (d, 1H), 6.94 (s, 1H), 7.28 (s, 1H), 7.45 (s, 1H), 7.69(s, 1H), 8.45 (br s, 1H) and 8.98 (s, 1H)

MS (ESI): 448 (MH)⁺

Elemental analysis Found C 64.0 H 6.4 N 14.4 C₂₅H₂₉N₅O₃.0.3 H₂O +Requires C 63.6 H 6.3 N 14.4% 0.4 dichloromethane

EXAMPLE 313

A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (227mg, 0.68 mmol), (prepared as described for the starting material inExample 67), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol),(prepared as described for the starting material in Example 182), andpotassium carbonate (350 mg, 2.5 mmol) in DMF (4 ml) was stirred at 95°C. for 6 hours and allowed to cool to ambient temperature. The reactionmixture was treated with 1.0 N aqueous sodium hydroxide solution andallowed to stir at ambient temperature for a few minutes. The resultingprecipitate was filtered off, washed with water and air dried to give acrude product. This was purified by column chromatography, elutinginitially with dichloromethane/methanol (85/15) to isolate a less polarimpurity and then with dichloromethane/methanol/0.88 ammonia (100/8/1)to isolate the target compound. The relevant fractions were combined andevaporated in vacuo to give a white solid which was triturated withacetone, filtered and dried to give6-methoxy-7-(3-piperidinopropoxy)4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline(58 mg, 20%).

¹H NMR Spectrum: (DMSO-d₆) 1.38 (m, 2H), 1.50 (m, 4H), 1.95 (m, 2H),2.15 (m, 4H), 2.42 (t, 2H), 3.99 (s, 3H), 4.22 (t, 2H), 6.47 (m, 1H),7.36 (s, 1H), 7.55 (m, 1H), 7.60 (s, 1H), 7.90 (d, 1H), 8.18 (d, 1H),8.49 (s, 1H) and 11.76 (br s, 1H)

MS (ESI): 434 (MH)⁺

Elemental analysis Found C 63.9 H 6.4 N 15.4 C₂₄H₂₇N₅O₃ 1.0 H₂O RequiresC 63.8 H 6.5 N 15.5%

EXAMPLE 314

To a solution of7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200 mg,0.47 mmol) in methylene chloride was added 4-piperidinopiperidine (237mg, 1.41 mmol) and the reaction heated at 40° C. for 1 hour. A furtherportion of 4-piperidinopiperidine (100 mg, 0.59 mmol) was added andreaction heated for a further 2 hours. The reaction was purified byflash chromatography eluting from methylene chloride to 15%methanol/methylene chloride (+1% ammonium hydroxide). The product wasevaporated, triturated with ether and filtered to give4-(indol-5-yloxy)-6-methoxy-7-(3-(4-piperidino)piperidinopropoxy)quinazoline(200 mg, 83%) as a yellow solid.

¹H NMR Spectrum: (CDCl₃) 1.48–2.18 (m, 19H), 2.58 (t, 2H), 3.06 (d, 2H),4.05 (s, 3H), 4.26 (t, 2H), 6.59 (s, 1H), 7.08 (dd, 1H), 7.28 (d, 1H),7.36 (s, 1H), 7.50 (d, 1H), 7.63 (s, 1H), 8.30 (s, 1H), 8.59 (s, 1H)

M S: 516 [MH]+

The starting material was prepared as follows:

To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (1g, 3.2 mmol), (prepared as described for the starting material inExample 107), in DMF (50 ml) was added powdered potassium carbonate(1.32 g, 9.6 mmol) and 1,3-dibromopropane (6.43 g, 32 mmol). Thereaction was heated at 50° C. for 2 hours. The inorganic material wasfiltered off and then the DMF removed. The residue was partitionedbetween methylene chloride/water. The organics were separated, driedover MgSO₄, filtered, evaporated in vacuo and purified by flashchromatography eluting from methylene chloride to 5% methanol/95%methylene chloride. The product was concentrated in vacuo, trituratedwith ether and the resulting solid filtered to give7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (900 mg,66%) as a white solid.

¹H NMR Spectrum: (CDCl₃) 2.46–2.57 (m, 2H), 3.68 (t, 2H), 4.08 (s, 3H),4.38 (t, 2H), 6.58 (s, 1H), 7.09 (d, 1H), 7.27 (s, 1H), 7.35 (s, 1H),7.46 (d, 1H), 7.50 (s, 1H), 7.63 (s, 1H), 8.30 (s, 1H), 8.62 (s, 1H)

MS: 428 [MH]+

EXAMPLE 315

To a solution of7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (225 ml,0.7 mmol), (prepared as described in Example 49), in DMF was addedpowdered potassium carbonate (290 mg, 2.1 mmol) and(5S)-5-(p-toluenesulphonylmethyl)-1-methyl-2-pyrrolidinone (340 mg, 1.2mmol). The reaction was then heated at 95° C. for 5 hours. The inorganicmaterial was filtered off and the DMF removed by evaporation. Theresidue was then purified by chromatography eluting from methylenechloride to 12% methanol/88% methylene chloride (+1% ammoniumhydroxide). The product was evaporated, triturated with ether andfiltered to give(5S)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(1-methyl-2-oxopyrrolidin-5-ylmethoxy)quinazoline(100 mg, 33%) as a white solid.

¹H NMR Spectrum: (DMSO-d₆) 1.84–1.96 (m, 1H), 2.10–2.30 (m, 2H), 2.39(s, 3H), 2.43–2.53 (m, 1H), 2.80 (s, 3H), 3.98 (s, 4H), 4.22 (dd, 1H),4.40 (dd, 1H), 6.10 (s, 1H), 6.84 (dd, 1H), 7.23 (d, 1H), 7.30 (d, 1H),7.40 (s, 1H), 7.59 (s, 1H), 8.49 (s, 1H), 10.98 (br s, 1H)

M S: 429 [MH]+

Elemental Analysis: Found C 64.4 H 5.4 N 12.6 C₂₄H₂₄N₄O₄ 0.8 H₂ORequires C 64.5 H 5.8 N 12.5%

The starting material was prepared as follows:

(5S)-5-(p-Toluenesulphonylmethyl)-2-pyrrolidinone (0.8 g, 3 mmol) wasdissolved in dry THF and cooled to −70° C. Lithium diisopropylamide wasslowly added and the reaction stirred for 20 minutes before addition ofmethyl iodide (2 ml, excess). The reaction was allowed to warm toambient temperature for over 2 hours. The reaction was partitionedbetween ethyl acetate and water, the organic layer separated, dried overMgSO₄, filtered, and evaporated in vacuo. The residue was purified byflash chromatography eluting from methylene chloride to 5% methanol/95%methylene chloride and the product evaporated to give(5S)-5-(p-toluenesulphonyl-methyl)-1-methyl-2-pyrrolidinone (340 mg,40%) as a brown oil.

¹H NMR Spectrum: (CDCl₃) 2.10–2.44 (m 4H), 2.48 (s, 3H), 2.76 (s, 3H),3.30–3.54 (m, 1H), 4.04 (dd, 1H), 4.15 (dd, 1H), 7.38 (d, 2H), 7.78 (d,2H)

M S: 284 [MH]+

EXAMPLE 316

To a solution of 7-hydroxy-4-(l H-indol-5-yloxy)-6-methoxyquinazoline(600 mg, 1.95 mmol), (prepared as described for the starting material inExample 107), in DMF (20 ml) was added powdered potassuim carbonate (540mg, 3.9 mmol) and (5S)-5-(p-toluene-sulphonylmethyl)-2-pyrrolidinone(580 mg, 2.16 mmol). The reaction was then heated at 100° C. for 4hours. The inorganic material was filtered off and the DMF removed byevaporation. The residue was then purified by chromatography elutingfrom methylene chloride to 12% methanol/88% methylene chloride (+1%ammonium hydroxide). The product was evaporated, triturated with ether,and filtered to give(5S)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline(240 mg, 31%) as a white solid.

¹H NMR Spectrum: (DMSO-d₆) 1.87–2.48 (m, 4H), 3.97 (s, 3H), 4.17 (m,2H), 6.45 (s, 1H), 6.96 (dd, 1H), 7.38–7.49 (m, 4H), 7.60 (s, 1H), 7.81(s, 1H), 8.50 (s, 1H)

M S: 405 [MH]+

EXAMPLE 317

To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline(800 mg, 2.6 mmol), (prepared as described for the starting material inExample 107), in DMF (20 ml) was added powdered potassuim carbonate(1.08 g, 7.8 mmol) and (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone(1.13 g, 4.2 mmol). The reaction was then heated at 90° C. for 4 hours.The inorganic material was filtered off and the DMF removed byevaporation. The residue was then purified by chromatography elutingfrom methylene chloride to 12% methanol/88% methylene chloride (+1%ammonium hydroxide). A small portion was recolumned using the samegradient. The product was evaporated, triturated with ether and filteredto give(5R)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline(70 mg, 6.5%) as a white solid.

¹H NMR Spectrum: (DMSO-d₆) 1.64–2.45 (m, 4H), 3.78 (m, 1H), 3.99 (s,3H), 4.18 (t, 2H), 6.42 (s, 1H), 6.97 (dd, 1H), 7.38–7.48 (m, 3H), 7.60(s, 1H), 7.73 (s, 2H), 8.48 (s, 1H), 11.18 (br s, 1H)

M S: 405 [MH]+

The starting material was prepared as follows:

To a solution of (5R)-5-hydroxymethyl-2-pyrrolidinone (5.0 g, 43 mmol)in methylene chloride (100 ml) was added 4-dimethylaminopyridine (15.7g, 129 mmol) and p-toluenesulphonyl chloride (9.0 g, 47 mmol). Thereaction was stirred at ambient temperature for 16 hours. The reactionwas then washed with 1M hydrochloric acid and the organic layerseparated. This was then dried over MgSO₄, filtered and evaporated togive (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (10.3 g, 89%) asa white solid.

¹H NMR Spectrum: (CDCl₃) 1.68–1.86 (m, 1H), 2.16–2.38 (m, 3H), 2.48 (s,3H), 3.86–3.96 (m, 2H), 4.08 (dd, 1H), 6.20 (br s, 1H), 7.38 (d, 2H),7.80 (d, 2H)

M S: 270 [MH]+

EXAMPLE 318

To a suspension of7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g,4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), wasadded potassium carbonate (2.34 g, 17.0 mmol, 4eq.) followed by(5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol,1.1 eq.), (prepared as described for the starting material in Example317), and the resulting yellow suspension heated at reflux. After 4hours, some starting material remained, and a further addition of(5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol,0.5eq.) was made. The reaction was heated at reflux for a further 2hours resulting in consumption of starting material. The reaction wascooled to ambient temperature, the inorganic residue filtered off andthe filtrate evaporated in vacuo to leave a brown oil which was purifiedby column chromatography (methylene chloride/methanol, (100/0 to 90/10))to give a light brown oil. Trituration with ether afforded a thick oil,which upon chromatography eluting as above gave a yellow oil.Trituration of this oil with ether gave an initial crop of(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline(5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography ofthe residues (eluting as above) followed by ether trituration gavefurther crops of(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazolineas a white solid (180 mg, >95% pure by nmr), as an off-white solid (800mg, ca. 95% pure by nmr).

¹H NMR Spectrum: (DMSOd₆) 1.8–2.2 (m, 5H), 2.4 (s, 3H), 4.0 (br s, 3H),4.1–4.2 (m, 2H), 6.1 (br s, 1H), 6.9 (dd, 1H), 7.2 (d, 1H), 7.3 (d, 1H),7.4 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H), 8.5 (s, 1H), 11.0 (br s, 1H)

MS: 419 [MH]⁺

Elemental analysis: Found C 60.8 H 5.3 N 12.1 C₂₃H₂₂N₄O₄ 2 H₂O RequiresC 60.8 H 5.7 N 12.3%

EXAMPLE 319

To a solution of7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (4.8 g,15.7 mmol), (prepared as described in Example 49), in DMF (100 ml), wasadded potassuim carbonate (6.5 g, 47 mmol) and 3-chloropropyl piperidine(3.3 g, 20.4 mmol). The reaction was then heated to 100° C. for 4 hours.The inorganic material was filtered off and the DMF removed byevaporation. The residue was then purified by chromatography elutingfrom methylene chloride to 10% methanol/90% methylene chloride (+1%ammonium hydroxide). The relevant fractions were concentrated and theresidue dissolved in ethyl acetate. Hexane was added and the precipitaewas filtered off. The filtrate was evaporated and the residue wastriturated with ether and filtered to give6-methoxy-4-(1-(3-piperidinopropyl)-1H-indol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline(170 mg, 1.9%) as a white solid.

¹H NMR Spectrum: (DMSO-d₆) 1.38 (br s, 4H), 1.50 (br s, 8H), 1.92 (m,4H), 2.14–2.48 (m, 12H), 3.98 (s, 3H), 4.24 (t, 4H), 6.43 (s, 1H), 7.02(d, 1H), 7.38 (s, 1H), 7.42 (s, 2H), 7.53 (d, 1H), 7.58 (s, 1H), 8.44(s, 1H)

M S: 558 [MH]+

EXAMPLE 320

A mixture of(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(6.201 g, 16.4 mmol), (prepared as described for the starting materialin Example 269), and piperidine (4.8 ml, 49.3 mmol) in DMF (100 ml) wasstirred at 60° C. for 24 hours and allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residue purifiedon silica gel, eluting with dichloromethane, dichloromethane/methanol(95/5) then dichloromethane/methanol/0.880 aqueous ammonia (89:10:1).The product was then recrystallised from acetonitrile to give(2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline(3.33 g, 44%) as an off-white solid.

¹H NMR Spectrum: (DMSO₆) 1.35 (m, 2H), 1.51 (m, 4H), 2.30–2.40 (m, 9H),3.98 (s, 3H), 4.08 (m, 2H), 4.21 (m, 1H), 4.86 (m, 1H), 6.10 (s, 1H),6.87 (dd, 1H), 7.25 (d, 1H) 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H),8.45 (s, 1H) and 10.98 (br s, 1H)

MS (ESI): 463 (MH)⁺

Elemental analysis: Found C 66.5 H 6.6 N 12.0 C₂₆H₃₀N₄O₄ 0.4 H₂ORequires C 66.5 H 6.6 N 11.9%

EXAMPLE 321

A mixture of(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline(175 mg 0.46 mmol), (prepared as described for the starting material inExample 304), and piperidine (0.14 ml, 1.39 mmol) in DMF (5 ml) wasstirred at 60° C. for 24 hours and allowed to cool to ambienttemperature. The solvents were removed in vacuo and the residue purifiedon silica gel, gradient elution eluting with dichloromethane,dichloromethane/methanol (95/5) then dichloromethane/methanol/0.880aqueous ammonia (89:10:1). The product was then recrystallised fromacetonitrile to give(2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline(88 mg, 41%) as an off-white solid.

¹H NMR Spectrum: (DMSO₆) 1.35 (m, 2H), 1.51 (m, 4H), 2.30–2.40 (m, 9H),3.98 (s, 3H), 4.08 (m, 2H), 4.21 (m, 1H), 4.86 (m, 1H), 6.10 (s, 1H),6.87 (dd, 1H), 7.25 (d, 1H) 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H),8.45 (s, 1H) and 10.98 (br s, 1H)

MS (ESI): 463 (MH)⁺

Elemental analysis: Found C 66.2 H 6.8 N 11.9 C₂₆H₃₀N₄O₄ 0.5 H₂ORequires C 66.2 H 6.6 N 11.9%

EXAMPLE 322

A solution of4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.22g, 3.65 mmol), (prepared as described for the starting material inExample 241), 4-fluoro-5-hydroxy-2-methylindole (723 mg, 4.38 mmol),(prepared as described for the starting material in Example 237), in DMF(20 ml) containing potassium carbonate (756 mg, 5.48 mmol) was stirredat 95° C. for 3 hours. After cooling, the mixture was filtered and thefiltrate was evaporated. The residue was purified by columnchromatography eluting with methylene chloride/methanol (9/1) followedby methylene chloride/methanol/methanol saturated with ammonia (90/5/5).The fractions containing the expected product were combined andevvaporated. The residue was triturated with ether, filtered, washedwith ether and dried under vacuum. The solid was dissolved in methylenechloride/ethyl acetate and the minimum of methanol, filtered and thevolatiles were removed under vacuum. The solid was triturated withether, filtered, washed with ether and dried under vacuum at 50° C. togive4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline(1.06 g, 62%).

MS-ESI 465 [MH]+

¹H NMR Spectrum: (DMSOd₆) 1.1–1.3 (m, 2H); 1.35–1.5 (m, 1H); 1.6–1.9 (m,6H); 2.12 (s, 3H); 2.4 (s, 3H); 2.75 (d, 2H); 3.95 (s, 3H); 4.22 (t,2H); 6.2 (s, 1H); 6.95 (dd, 1H); 7.15 (d, 1H); 7.4 (s, 1H); 7.6 (s, 1H);8.5 (s, 1H)

EXAMPLE 323

Sodium hydride (71 mg, 1.8 mmol) was added to5-hydroxy-2-methylbenzimidazole (204 mg, 0.89 mmol) in anhydrous DMF(2.5 ml) under an argon atmosphere. The mixture was stirred at ambienttemperature for 10 minutes. 4-Chloro-6,7-dimethoxyquinazoline (200 mg,0.89 mmol) was added and the reaction mixture stirred at 95° C. for 2hours. Upon cooling to ambient temperature the mixture was poured inwater and extracted with ethyl acetate. The organic phase was washedwith brine, dried (MgSO₄), silica was added and the solvent evaporatedoff. The obtained powder was placed on the top of a disposable silicacolumn (ISOLUTE) and the product eluted off using a gradient ofmethanol/dichloromethane (3/97, 5/95, 8/92). Evaporation of the solventgave 6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)quinazoline (145mg, 48%).

¹H NMR Spectrum: (DMSOd₆) 2.50 (s, 3H); 3.95 (s, 3H); 4.0 (s, 3H); 7.05(d, 1H); 7.38 (s, 1H); 7.39 (d, 1H); 7.51 (d, 1H); 7.60 (s,1H); 8.50(s,1H)

MS (ESI): 337 [MH]⁺

EXAMPLE 324

7-Hydroxyquinazoline (87 mg, 0.6 mmol) and potassium carbonate (110 mg,0.8 mmol) were added to4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (180 mg, 0.53mmol), prepared as described for the starting material in Example 1), insuspension in DMF (3 ml) under an argon atmosphere. The reaction mixturewas heated to 100° C. for 90 minutes. Upon cooling to ambienttemperature the reaction was diluted with ethyl acetate and a saturatedammonium chloride solution. The aqueous phase was re-extracted withethyl acetate, the organic phases combined, dried (MgSO₄) and thesolvent evaporated. The residue was purified by flash chromatographyusing a gradient of methanol/dichloromethane (3/97, 4/96, 5/95).Evaporation of the solvent and trituration of the solid with ether gave6-methoxy-7-(3-morpholinopropoxy)-4-(quinazolin-7-yloxy)quinazoline (197mg, 83%).

¹H NMR Spectrum (DMSOd₆) 2.01 (t, 2H); 2.47 (m, 4H); 2.49 (m, 2H); 3.60(m, 4H); 4.01 (s, 3H); 4.29 (t, 2H); 7.45 (s, 1H); 7.65 (s, 1H); 7.80(d, 1H); 8.01 (d, 1H); 8.32 (d, 1H); 8.60 (s, 1H); 9.34 (s, 1H); 9.69(s, 1H)

MS (ESI): 448 [MH]⁺

Elemental analysis: Found C 63.4 H 5.7 N 15.6 C₂₄H₂₅N₅O₄; 0.4 H₂ORequires C 63.4 H 5.7 N 15.4%

The starting material was prepared as follows:

Raney Nickel (about 200 mg), (prewashed several times with ethanol), wasadded to a solution of 7-hydroxy-4-thiomethylquinazoline (400 mg, 2.08mmol), (Tet. Lett. 1999, 40, 3881), and the solution was refluxed for 1hour. Raney Nickel (100 mg) was added and the mixture was refluxed for afurther 1 hour. The mixture was filtered, washed with ethanol and thevolatiles were removed under vacuum. The residue was purified by columnchromatography eluting with methylene chloride/methanol (97/3 followedby 96/4) to give 7-hydroxyquinazoline (62 mg, 20%).

EXAMPLE 325

Using an analogous procedure to that described in Example 201,7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol),(prepared as described for the starting material in Example 217), wasreacted with 5-(2-hydroxyethyl)-4-methylthiazole (69 mg, 0.48 mmol) togive6-methoxy-4-(indol-6-ylamino)-7-(2-(4-methylthiazol-5-yl)ethoxy)quinazoline(47 mg, 34%).

MS-ESI: 432 [MH]⁺

¹H NMR Spectrum: (DMSOd₆) 2.4 (s, 3H); 3.3 (t, 2H); 4.0 (s, 3H); 4.35(t, 2H); 6.45 (s, 1H); 7.2 (s, 1H); 7.25–7.4 (m, 2H); 7.55 (d, 1H); 7.9(s, 1H); 8.05 (s, 1H); 8.45 (s, 1H) 8.87 (s, 1H); 9.45 (s, 1H)

EXAMPLE 326

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesiumstearate 1.5 (e) Injection I (50 mg/ml) Compound X  5.0% w/v 1N Sodiumhydroxide solution 15.0% v/v 0.1N Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400  4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X  1.0% w/v Sodium phosphate BP  3.6%w/v 0.1N Sodium hydroxide solution 15.0% v/v Water for injection to 100%(g) Injection III (1 mg/ml, buffered to pH6) Compound X  0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100% Note The above formulations may beobtained by conventional procedures well known in the pharmaceuticalart. The tablets (a)–(c) may be enteric coated by conventional means,for example to provide a coating of cellulose acetate phthalate.

1. A compound of the formula II:

wherein: ring C is a 9 or 10-membered heteroaromatic bicyclic moietywhich contains 1–3 heteroatoms selected independently from O, N and S;Zb is —O— or —S—; n is an integer from 0 to 5; R² represents hydroxy,halogeno, cyano, nitro, trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl), or R² represents agroup R⁵X¹—, wherein X¹ represents a direct bond, —O—, —CH₂—, —OC(O)—,—C(O)—, —S—, —SO—, —SO₂—, —NR⁶C(O)—, —C(O)NR⁷—, —SO₂NR⁸—, —NR⁹SO₂— or—NR¹⁰— (wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), and R⁵ is selected from oneof the following twenty-two groups: 1) hydrogen, oxiranylC₁₋₄alkyl orC₁₋₅alkyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro, chloro, bromo andamino; 2) C₁₋₅alkylX²C(O)R¹¹ (wherein X² represents —O— or —NR¹²— (inwhich R¹² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹¹represents C₁₋₃alkyl, —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ whichmay be the same or different each represents hydrogen, C₁₋₅alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX³R¹⁶ (wherein X³ represents —O—,—S—, —SO—, —SO₂—, —OC(O)—, —NR¹⁷C(O)—, —C(O)NR¹⁸—, —SO₂NR¹⁹—, —NR²⁰SO₂—or —NR²¹— (wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selectedindependently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy andwhich cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 4)C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²² (wherein X⁴ and X⁵ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR²³C(O)—, —C(O)NR²⁴—,—SO₂NR²⁵—, —NR²⁶SO₂— or —NR²⁷— (wherein R²³, R²⁴, R²⁵, R²⁶ and R²⁷ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl); 5) R²⁸(wherein R²⁸ is a 4–6-membered saturated heterocyclic group (linked viacarbon or nitrogen) with 1–2 heteroatoms, selected independently from O,S and N, which heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-membered saturatedheterocyclic group with 1–2 heteroatoms, selected independently from O,S and N, which cyclic group may bear one or more substituents selectedfrom C₁₋₄alkyl)); 6) C₁₋₅alkylR²⁸ (wherein R²⁸ is as defined herein); 7)C₂₋₅alkenylR²⁸ (wherein R²⁸ is as defined herein); 8) C₂₋₅alkynylR²⁸(wherein R²⁸ is as defined herein); 9) R²⁹ (wherein R²⁹ represents apyridone group, a phenyl group or a 5–6-membered aromatic heterocyclicgroup (linked via carbon or nitrogen) with 1–3 heteroatoms selected fromO, N and S, which pyridone, phenyl or aromatic heterocyclic group maycarry up to 5 substituents selected from hydroxy, halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR³⁰R³¹,—NR³²C(O)R³³ (wherein R³⁰, R³¹, R³² and R³³, which may be the same ordifferent, each represents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0or 1 and ring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 10)C₁₋₅alkylR²⁹ (wherein R²⁹ is as defined herein); 11) C₂₋₅alkenylR²⁹(wherein R²⁹ is as defined herein); 12) C₂₋₅alkynylR²⁹ (wherein R²⁹ isas defined herein); 13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ represents —O—, —S—,—SO—, —SO₂—, —NR³⁴C(O)—, —C(O)NR³⁵—, —SO₂NR³⁶—, —NR³⁷SO₂— or—NR³⁸—(wherein R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as definedherein); 14) C₂₋₅alkenylX⁷R²⁹ (wherein X⁷ represents —O—, —S—, —SO—,—SO₂—, —NR³⁹C(O)—, —C(O)NR⁴⁰—, —SO₂NR⁴¹—, —NR⁴²SO₂— or —NR⁴³— (whereinR³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 15)C₂₋₅alkynylX⁸R²⁹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,—NR⁴⁴C(O)—, —C(O)NR⁴⁵—, —SO₂NR⁴⁶—, —NR⁴⁷SO₂— or —NR⁴⁸— (wherein R⁴⁴,R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 16)C₁₋₄alkylX⁹C₁₋₄alkylR²⁹ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁴⁹C(O)—, —C(O)NR⁵⁰—, —SO₂NR⁵¹—, —NR⁵²SO₂— or —NR⁵³— (wherein R⁴⁹,R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²⁹ is as defined herein); 17)C₁₋₄alkylX⁹C₁₋₄alkylR²⁸ (wherein X⁹ and R²⁸ are as defined herein); 18)C₂₋₅alkenyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 19) C₂₋₅alkynyl which may beunsubstituted or which may be substituted with one or more groupsselected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 20) C₂₋₅alkenylX⁹C₁₋₄alkylR²⁸ (whereinX⁹ and R²⁸ are as defined herein); 21) C₂₋₅alkynylX⁹C₁₋₄alkylR²⁸(wherein X⁹ and R²⁸ are as defined herein); and 22)C₁₋₄alkylR⁵⁴(C₁₋₄alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹ is as defined herein,q is 0 or 1, r is 0 or 1, and R⁵⁴ and R⁵⁵ are each independentlyselected from hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl and a4–6-membered saturated heterocyclic group with 1–2 heteroatoms, selectedindependently from O, S and N, which C₁₋₃alkyl group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy andwhich cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl), with theproviso that R⁵⁴ cannot be hydrogen); and additionally wherein anyC₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one ormore substituents selected from hydroxy, halogeno and amino; R¹represents hydrogen, oxo, halogeno, hydroxy, C₁₋₄alkoxy, C₁₋₄alkyl,C₁₋₄alkoxymethyl, C₁₋₄alkanoyl, C₁₋₄haloalkyl, cyano, amino,C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₃alkanoyloxy, nitro, C₁₋₄alkanoylamino,C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphinyl,C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, N—(C₁₋₄alkylsulphonyl)amino,N—(C₁₋₄alkylsulphonyl)-N—(C₁₋₄alkyl)amino,N,N-di(C₁₋₄alkylsulphonyl)amino, a C₃₋₇alkylene chain joined to two ringC carbon atoms, C₁₋₄alkanoylaminoC₁₋₄alkyl, carboxy, or R¹ represents agroup R⁵⁶X¹⁰, wherein X¹⁰ represents a direct bond, —O—, —CH₂—, —OC(O)—,—C(O)—, —S—, —SO—, —SO₂—, —NR⁵⁷C(O)—, —C(O)NR⁵⁸—, —SO₂NR⁵⁹—, —NR⁶⁰SO₂—or —NR⁶¹— (wherein R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰ and R⁶¹ each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), and R⁵⁶ isselected from one of the following twenty-two groups: 1) hydrogen,oxiranylC₁₋₄alkyl or C₁₋₅alkyl which may be unsubstituted or which maybe substituted with one or more groups selected from hydroxy, fluoro,chloro, bromo and amino; 2) C₁₋₅alkylX¹¹C(O)R⁶² (wherein X¹¹ represents—O— or —NR⁶³— (in which R⁶³ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R⁶² represents C₁₋₃alkyl, —NR⁶⁴R⁶⁵ or —OR⁶⁶(wherein R⁶⁴, R⁶⁵ and R⁶⁶ which may be the same or different eachrepresents hydrogen, C₁₋₅alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3)C₁₋₅alkylX¹²R⁶⁷ (wherein X¹² represents —O—, —S—, —SO—, —SO₂—, —OC(O)—,—NR⁶⁸C(O)—, —C(O)NR⁶⁹—, —SO₂NR⁷⁰—, —NR⁷¹SO₂— or —NR⁷²— (wherein R⁶⁸,R⁶⁹, R⁷⁰, R⁷¹, and R⁷² each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R⁶⁷ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 4–6-membered saturated heterocyclic groupwith 1–2 heteroatoms, selected independently from O, S and N, whichC₁₋₃alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno and C₁₋₄alkoxy and which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 4)C₁₋₅alkylX¹³C₁₋₅alkylX¹⁴R⁷³ (wherein X¹³ and X¹⁴ which may be the sameor different are each —O—, —S—, —SO—, —SO₂—, —NR⁷⁴C(O)—, —C(O)NR⁷⁵—,—SO₂NR⁷⁶—, —NR⁷⁷SO₂— or —NR⁷⁸— (wherein R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷ and R⁷⁸ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR⁷³ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl); 5) R⁷⁹(wherein R⁷⁹ is a 4–6-membered saturated heterocyclic group (linked viacarbon or nitrogen) with 1–2 heteroatoms, selected independently from O,S and N, which heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a 4–6-membered saturatedheterocyclic group with 1–2 heteroatoms, selected independently from O,S and N, which cyclic group may bear one or more substituents selectedfrom C₁₋₄alkyl)); 6) C₁₋₅alkylR⁷⁹ (wherein R⁷⁹ is as defined herein); 7)C₂₋₅alkenylR⁷⁹ (wherein R⁷⁹ is as defined herein); 8) C₂₋₅alkynylR⁷⁹(wherein R⁷⁹ is as defined herein); 9) R⁸⁰ (wherein R⁸⁰ represents apyridone group, a phenyl group or a 5–6-membered aromatic heterocyclicgroup (linked via carbon or nitrogen) with 1–3 heteroatoms selected fromO, N and S, which pyridone, phenyl or aromatic heterocyclic group maycarry up to 5 substituents selected from hydroxy, halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR⁸¹R⁸²,—NR⁸³C(O)R⁸⁴ (wherein R⁸¹, R⁸², R⁸³ and R⁸⁴, which may be the same ordifferent, each represents hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0or 1 and ring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl)); 10)C₁₋₅alkylR⁸⁰ (wherein R⁸⁰ is as defined herein); 11) C₂₋₅alkenylR⁸⁰(wherein R⁸⁰ is as defined herein); 12) C₂₋₅alkynylR⁸⁰ (wherein R⁸⁰ isas defined herein); 13) C₁₋₅alkylX¹⁵R⁸⁰ (wherein X¹⁵ represents —O—,—S—, —SO—, —SO₂—, —NR⁸⁵C(O)—, —C(O)NR⁸⁶—, —SO₂NR⁸⁷—, —NR⁸⁸SO₂— or —NR⁸⁹—(wherein R⁸⁵, R⁸⁶, R⁸⁷, R⁸⁸ and R⁸⁹ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as definedherein); 14) C₂₋₅alkenylX¹⁶R⁸⁰ (wherein X¹⁶ represents —O—, —S—, —SO—,—SO₂—, —NR⁹⁰C(O)—, —C(O)NR⁹¹—, —SO₂NR⁹²—, —NR⁹³SO₂— or —NR⁹⁴— (whereinR⁹⁰, R⁹¹, R⁹², R⁹³ and R⁹⁴ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined herein); 15)C₂₋₅alkynylX¹⁷R⁸⁰ (wherein X¹⁷ represents —O—, —S—, —SO—, —SO₂—,—NR⁹⁵C(O)—, —C(O)NR⁹⁶—, —SO₂NR⁹⁷—, —NR⁹⁸SO₂— or —NR⁹⁹— (wherein R⁹⁵,R⁹⁶, R⁹⁷, R⁹⁸ and R⁹⁹ each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined herein); 16)C₁₋₄alkylX¹⁸C₁₋₄alkylR⁸⁰ (wherein X¹⁸ represents —O—, —S—, —SO—, —SO₂—,—NR¹⁰⁰C(O)—, —C(O)NR¹⁰¹—, —SO₂NR¹⁰²—, —NR¹⁰³SO₂— or —NR¹⁰⁴— (whereinR¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰³ and R¹⁰⁴ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁸⁰ is as defined herein); 17)C₁₋₄alkylX¹⁸C₁₋₄alkylR⁷⁹ (wherein X¹⁸ and R⁷⁹ are as defined herein);18) C₂₋₅alkenyl which may be unsubstituted or which may be substitutedwith one or more groups selected from hydroxy, fluoro, amino,C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl; 19)C₂₋₅alkynyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, fluoro, amino, C₁₋₄alkylamino,N,N-di(C₁₋₄alkyl)amino, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 20) C₂₋₅alkenylX¹⁸C₁₋₄alkylR⁷⁹ (whereinX¹⁸ and R⁷⁹ are as defined herein); 21) C₂₋₅alkynylX¹⁸C₁₋₄alkylR⁷⁹(wherein X¹⁸ and R⁷⁹ are as defined herein); and 22)C₁₋₄alkylR¹⁰⁵(C₁₋₄alkyl)_(x)(X¹⁸)_(y)R¹⁰⁶ (wherein X¹⁸ is as definedherein, x is 0 or 1, y is 0 or 1, and R¹⁰⁵ and R¹⁰⁶ are eachindependently selected from hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyland a 4–6-membered saturated heterocyclic group with 1–2 heteroatoms,selected independently from O, S and N, which C₁₋₃alkyl group may bear 1or 2 substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxyand which cyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl) with theproviso that R¹⁰⁵ cannot be hydrogen); and additionally wherein anyC₁₋₅alkyl, C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵⁶X¹⁰— may bear one ormore substituents selected from hydroxy, halogeno and amino; R^(2a)represents hydrogen, halogeno, C₁₋₃alkyl, trifluoromethyl, C₁₋₃alkoxy,C₁₋₃alkylsulphanyl, —NR^(3a)R^(4a) (wherein R^(3a) and R^(4a), which maybe the same or different, each represents hydrogen or C₁₋₃alkyl), orR^(5a)(CH₂)_(za)X^(1a) (wherein R^(5a) is a 4-, 5- or 6-memberedsaturated heterocyclic group with 1–2 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a 4–6-membered saturated heterocyclic group with 1–2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from C₁₋₄alkyl), za is aninteger from 0 to 4 and X^(1a) represents a direct bond, —O—, —CH₂—,—S—, —SO—, —SO₂—, —NR^(6a)C(O)—, —C(O)NR^(7a)—, —SO₂NR^(8a)—,—NR^(9a)SO₂— or —NR^(10a)— (wherein R^(6a), R^(7a), R^(8a), R^(9a) andR^(10a) each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); or a salt thereof, with the proviso that R² isnot hydrogen.
 2. A compound of the formula II according to claim 1wherein R² represents hydroxy, halogeno, cyano, nitro, trifluoromethyl,C₁₋₃alkyl, amino or R⁵X¹—, wherein X¹ is as defined in claim 1 and R⁵ isselected from one of the following twenty-two groups: 1) C₁₋₄alkyl whichmay be unsubstituted or which may be substituted with one or more groupsselected from fluoro, chloro and bromo, or C₂₋₅alkyl which may beunsubstituted or substituted with one or more groups selected fromhydroxy and amino; 2) C₂₋₃alkylX²C(O)R¹¹ (wherein X² is as defined inclaim 1 and R¹¹ represents —NR¹³R¹⁴ or —OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵which may be the same or different are each C₁₋₄alkyl orC₁₋₂alkoxyethyl)); 3) C₂₋₄alkylX³R¹⁶ (wherein X³ is as defined in claim1 and R¹⁶ is a group selected from C₁₋₃alkyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl andtetrahydropyranyl, which C₁₋₃alkyl group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno and C₁₋₂ alkoxy and whichcyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl,imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃alkoxy,C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl)); 4)C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²² (wherein X⁴ and X⁵ are as defined in claim 1and R²² represents hydrogen or C₁₋₃alkyl); 5) R²⁸ (wherein R²⁸ is asdefined in claim 1); 6) C₁₋₄alkylR¹¹⁰ (wherein R¹¹⁰ is a group selectedfrom pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl,azetidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and1,3-dithian-2-yl, which group is linked to C₁₋₄alkyl through a carbonatom and which group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl, C₁₋₂alkylsulphonylC₁₋₃alkyl,C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃alkyl)amino,C₁₋₃alkylaminoC₁₋₃alkyl, di(C₁₋₃alkyl)aminoC₁₋₃alkyl,C₁₋₃alkylaminoC₁₋₃alkoxy, di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group—(—O—)_(f)(C₁₋₃alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl,piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino,which cyclic group may bear one or more substituents selected fromC₁₋₃alkyl)) or C₂₋₄alkylR¹¹¹ (wherein R¹¹¹ is a group selected frommorpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl,piperazin-1-yl and piperidino which group may bear 1 or 2 substituentsselected from oxo, hydroxy, halogeno, cyano, C₁₋₃cyanoalkyl, C₁₋₃alkyl,C₁₋₃hydroxyalkyl, C₁₋₃alkoxy, C₁₋₂alkoxyC₁₋₃alkyl,C₁₋₂alkylsulphonylC₁₋₃alkyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylamino,di(C₁₋₃alkyl)amino, C₁₋₃alkylaminoC₁₋₃alkyl,di(C₁₋₃alkyl)aminoC₁₋₃alkyl, C₁₋₃alkylaminoC₁₋₃alkoxy,di(C₁₋₃alkyl)aminoC₁₋₃alkoxy and a group —(—O—)_(f)(C₁₋₃alkyl)_(g)ringD(wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic groupselected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,azetidinyl, morpholino and thiomorpholino, which cyclic group may bearone or more substituents selected from C₁₋₃alkyl)); 7) C₃₋₄alkenylR¹¹²(wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined herein); 8)C₃₋₄alkynylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as definedherein); 9) R²⁹ (wherein R²⁹ is as defined in claim 1); 10) C₁₋₄alkylR²⁹(wherein R²⁹ is as defined in claim 1); 11) 1-R²⁹prop-1-en-3-yl or1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined in claim 1 with theproviso that when R⁵ is 1-R²⁹prop-1-en-3-yl, R²⁹ is linked to thealkenyl group via a carbon atom); 12) 1-R²⁹prop-1-yn-3-yl or1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined in claim 1 with theproviso that when R⁵ is 1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to thealkynyl group via a carbon atom); 13) C₁₋₅alkylX⁶R²⁹ (wherein X⁶ and R²⁹are as defined in claim 1); 14) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ andR²⁹ are as defined in claim 1); 15) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸and R²⁹ are as defined in claim 1); 16) C₂₋₃alkylX⁹C₁₋₃alkylR²⁹ (whereinX⁹ and R²⁹ are as defined in claim 1); 17) C₂₋₃alkylX⁹C₁₋₃alkylR²⁸(wherein X⁹ and R²⁸ are as defined in claim 1); 18) C₂₋₅alkenyl whichmay be unsubstituted or which may be substituted with one or morefluorine atoms or with one or two groups selected from hydroxy, fluoro,amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl; 19)C₂₋₅alkynyl which may be unsubstituted or which may be substituted withone or more fluorine atoms or with one or two groups selected fromhydroxy, fluoro, amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino,aminosulphonyl, N—C₁₋₄alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl; 20) C₂₋₄alkenylX⁹C₁₋₃alkylR²⁸ (whereinX⁹ and R²⁸ are as defined in claim 1); 21) C₂₋₄alkynylX⁹C₁₋₃alkylR²⁸(wherein X⁹ and R²⁸ are as defined in claim 1); and 22)C₁₋₃alkylR⁵⁴(C₁₋₃alkyl)_(q)(X⁹)_(r)R⁵⁵ (wherein X⁹, q, r, R⁵⁴ and R⁵⁵are as defined in claim 1); and additionally wherein any C₁₋₅alkyl,C₂₋₅alkenyl or C₂₋₅alkynyl group in R⁵X¹— may bear one or moresubstituents selected from hydroxy, halogeno and amino.
 3. A compoundaccording to claim 1 wherein Zb is —O—.
 4. A compound according to claim1 wherein R¹ represents oxo, halogeno, hydroxy, C₁₋₂alkoxy, C₁₋₂alkyl,C₁₋₂alkoxymethyl, C₂₋₃alkanoyl, C₁₋₂haloalkyl, cyano, amino,C₂₋₄alkenyl, C₂₋₄alkynyl, C₂₋₃alkanoyloxy, nitro, C₂₋₃alkanoylamino,C₁₋₂alkoxycarbonyl, C₁₋₂alkylsulphanyl, C₁₋₂alkylsulphinyl,C₁₋₂alkylsulphonyl, carbamoyl, N—C₁₋₂alkylcarbamoyl,N,N-di(C₁₋₂alkyl)carbamoyl, aminosulphonyl, N—C₁₋₂alkylaminosulphonyl,N,N-di(C₁₋₂alkyl)aminosulphonyl, N—(C₁₋₂alkylsulphonyl)amino,N—(C₁₋₂alkylsulphonyl)-N—(C₁₋₂alkyl)amino or a C₃₋₇alkylene chain joinedto two ring C carbon atoms.
 5. A compound according to claim 1 wherein nis 0, 1 or
 2. 6. A compound according to claim 1 wherein Zb is —O—, withthe proviso that R² is not substituted or unsubstituted C₁₋₅alkyl,halogeno, C₁₋₅alkoxy, C₂₋₅alkenyl, phenoxy or phenylC₁₋₅alkoxy.
 7. Acompound according to claim 1 selected from6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,(R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline,7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline,7-(3-(,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxy-quinazoline,4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline, 7-(2-(N,N-diethyl amino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline,4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy) quinazoline,7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline,and7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,or a salt thereof.
 8. A compound according to claim 1 selected from6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(pip eridin-4-yloxy)ethoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline,7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline,4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,7-(3-(N,N-dimethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline,4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,(2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline,(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline,4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline,(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,(2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,(2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,(2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,(2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline,4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline,(2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline,and4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline, or a salt thereof.
 9. A compound according to claim 1selected from6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline,and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,or a salt thereof.
 10. A compound according to claim 1 in the form of apharmaceutically acceptable salt.
 11. A compound according to claim 1wherein ring C is selected from indolyl and quinolinyl.
 12. The compound4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline, or a salt thereof.
 13. A compound according to claim 9which is6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,or a salt thereof.
 14. A compound according to claim 9 which is4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,or a salt thereof.
 15. A compound according to claim 9 which is4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,or a salt thereof.
 16. A compound according to claim 9 which is4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,or a salt thereof.
 17. A compound according to claim 9 which is4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,or a salt thereof.
 18. A compound according to claim 9 which is4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,or a salt thereof.
 19. A compound according to claim 9 which is4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,or a salt thereof.
 20. A compound according to claim 9 which is4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,or a salt thereof.
 21. A compound according to claim 9 which is4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,or a salt thereof.
 22. A compound according to claim 9 which is4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,or a salt thereof.
 23. A compound according to claim 9 which is(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline,or a salt thereof.
 24. A compound according to claim 9 which is4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,or a salt thereof.
 25. A pharmaceutical composition which comprises asactive ingredient a compound of formula II or a pharmaceuticallyacceptable salt thereof according to any one of claims 1–3, 4–9 and 11in association with a pharmaceutically acceptable excipient or carrier.26. A method for inhibiting VEGF receptor tyrosine kinase activity in awarm-blooded animal in need thereof comprising administering to saidanimal an inhibiting amount of a compound of the formula II as definedin any one of claims 1–3, 4–9 and 11 or a pharmaceutically acceptablesalt thereof.